B-superfamily conotoxins

ABSTRACT

The present invention is directed to β-superfamily conotoxin peptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand gated channels and other receptors. The invention is further directed to nucleic acid sequences encoding the β-superfamily conotoxin peptides and encoding β-superfamily conotoxin propeptides, as well as the β-superfamily conotoxin propeptides.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application is a continuation of U.S. patentapplication Ser. No. 10/058,053 filed on 29 Jan. 2002. The presentapplication is also related to and claims priority under 35 USC § 119(e)to U.S. provisional patent application Serial No. 60/264,323 filed on 29Jan. 2001. Each application is incorporated herein by reference.

[0002] This invention was made with Government support under Grant No.PO1 GM48677 awarded by the National Institute of General MedicalSciences, National Institutes of Health, Bethesda, Md. The United StatesGovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] The present invention is directed to β-superfamily conotoxinpeptides (also referred to as β-conotoxins), derivatives orpharmaceutically acceptable salts thereof. The present invention isfurther directed to the use of this peptide, derivatives thereof andpharmaceutically acceptable salts thereof for the treatment of disordersassociated with voltage-gated ion channels, ligand-gated ion channelsand/or receptors. The invention is further directed to nucleic acidsequences encoding the conotoxin peptides and encoding propeptides, aswell as the propeptides.

[0004] The publications and other materials used herein to illuminatethe background of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference, and for convenience are referenced in the following text byauthor and date and are listed alphabetically by author in the appendedbibliography.

[0005] Conus is a genus of predatory marine gastropods (snails) whichenvenomate their prey. Venomous cone snails use a highly developedprojectile apparatus to deliver their cocktail of toxic conotoxins intotheir prey. In fish-eating species such as Conus magus the cone detectsthe presence of the fish using chemosensors in its siphon. When closeenough it extends its proboscis and impales the fish hollow harpoon-liketooth containing venom. This immobilizes the fish and enables the conesnail to wind it into its mouth via the tooth at the end of theproboscis. For general information on Conus and their venom see thewebsite address grimwade.biochem.unimelb. edu.au/cone/referenc.html.Prey capture is accomplished through a sophisticated arsenal of peptideswhich target specific ion channel and receptor subtypes. Each Conusspecies venom appears to contain a unique set of 50-200 peptides. Thecomposition of the venom differs greatly between species and betweenindividual snails within each species, each optimally evolved toparalyse it's prey. The active components of the venom are smallpeptides toxins, typically 10-30 amino acid residues in length and aretypically highly constrained peptides due to their high density ofdisulphide bonds.

[0006] The venoms consist of a large number of different peptidecomponents that when separated exhibit a range of biological activities:when injected into mice they elicit a range of physiological responsesfrom shaking to depression. The paralytic components of the venom thathave been the focus of recent investigation are the α-, ω- andμ-conotoxins. All of these conotoxins act by preventing neuronalcommunication, but each targets a different aspect of the process toachieve this. The α-conotoxins target nicotinic ligand gated channels,the μ-conotoxins target the voltage-gated sodium channels and theω-conotoxins target the voltage-gated calcium channels (Olivera et al.,1985; Olivera et al., 1990). For example a linkage has been establishedbetween α-, αA- & ψ-conotoxins and the nicotinic ligand-gated ionchannel; co-conotoxins and the voltage-gated calcium channel;κ-conotoxins and the voltage-gated sodium channel; δ-conotoxins and thevoltage-gated sodium channel; κ-conotoxins and the voltage-gatedpotassium channel; conantokins and the ligand-gated glutamate (NMDA)channel.

[0007] However, the structure and function of only a small minority ofthese peptides have been determined to date. For peptides where functionhas been determined, three classes of targets have been elucidated:voltage-gated ion channels; ligand-gated ion channels, andG-protein-linked receptors.

[0008] Conus peptides which target voltage-gated ion channels includethose that delay the inactivation of sodium channels, as well asblockers specific for sodium channels, calcium channels and potassiumchannels. Peptides that target ligand-gated ion channels includeantagonists of NMDA and serotonin receptors, as well as competitive andnoncompetitive nicotinic receptor antagonists. Peptides which act onG-protein receptors include neurotensin and vasopressin receptoragonists. The unprecedented pharmaceutical selectivity of conotoxins isat least in part defined by a specific disulfide bond frameworkscombined with hypervariable amino acids within disulfide loops (for areview see McIntosh et al., 1998).

[0009] There are drugs used in the treatment of pain, which are known inthe literature and to the skilled artisan. See, for example, MerckManual, 16th Ed. (1992). However, there is a demand for more activeanalgesic agents with diminished side effects and toxicity and which arenon-addictive. The ideal analgesic would reduce the awareness of pain,produce analgesia over a wide range of pain types, act satisfactorilywhether given orally or parenterally, produce minimal or no sideeffects, be free from tendency to produce tolerance and drug dependence.

[0010] Due to the high potency and exquisite selectivity of theconopeptides, several are in various stages of clinical development fortreatment of human disorders. For example, two Conus peptides are beingdeveloped for the treatment of pain. The most advanced is co-conotoxinMVIIA (ziconotide), an N-type calcium channel blocker (see Heading, C.,1999; U.S. Pat. No. 5,859,186). ω-Conotoxin MVIIA, isolated from Conusmagus, is approximately 1000 times more potent than morphine, yet doesnot produce the tolerance or addictive properties of opiates.ω-Conotoxin MVIIA has completed Phase III (final stages) of humanclinical trials and has been approved as a therapeutic agent.ω-Conotoxin MVIIA is introduced into human patients by means of animplantable, programmable pump with a catheter threaded into theintrathecal space. Preclinical testing for use in post-surgical pain isbeing carried out on another Conus peptide, contulakin-G, isolated fromConus geographus (Craig et al. 1999). Contulakin-G is a 16 amino acidO-linked glycopeptide whose C-terminus resembles neurotensin. It is anagonist of neurotensin receptors, but appears significantly more potentthan neurotensin in inhibiting pain in in vivo assays.

[0011] In view of a large number of biologically active substances inConus species it is desirable to further characterize them and toidentify peptides capable of treating disorders voltage-gated ionchannels, ligand-gated ion channels and/or receptors. Surprisingly, andin accordance with this invention, Applicants have discovered novelconotoxins that can be useful for the treatment of disorders involvingvoltage-gated ion channels, ligand-gated ion channels and/or receptorsand could address a long felt need for a safe and effective treatment.

SUMMARY OF THE INVENTION

[0012] The present invention is directed to conotoxin peptides,derivatives or pharmaceutically acceptable salts thereof. The presentinvention is further directed to the use of this peptide, derivativesthereof and pharmaceutically acceptable salts thereof for the treatmentof disorders associated with voltage-gated ion channels, ligand-gatedion channels and/or G-protein coupled receptors (GPCRs). The inventionis further directed to nucleic acid sequences encoding the conotoxinpeptides and encoding propeptides, as well as the propeptides.

[0013] More specifically, the present invention is directed to conotoxinpeptides, having the amino acid sequences set forth in Tables 1-3 below.In the β-superfamily conotoxins containing 4-Cys residues (e.g.,Ge14.1), the peptide may be bridged [1,4/2,3] or [1,3/2,4].

[0014] The present invention is also directed to derivatives orpharmaceutically acceptable salts of the conotoxin peptides or thederivatives. Examples of derivatives include peptides in which the Argresidues may be substituted by Lys, ornithine, homoarginine, nor-Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any syntheticbasic amino acid. The Lys residues may be substituted by Arg, omithine,homoarginine, nor-Lys, or any synthetic basic amino acid. The Tyrresidues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, ¹²⁵I-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr orany synthetic hydroxy containing amino acid. The Ser residues may besubstituted with Thr or any synthetic hydroxylated amino acid. The Thrresidues may be substituted with Ser or any synthetic hydroxylated aminoacid. The Phe residues may be D or L, may be substituted at the ortho,meta, and/or para positions with a halogen or may be substituted withany synthetic aromatic amino acid. The Trp residues may be substitutedwith Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or anyaromatic synthetic amino acid; and the Asn, Ser, Thr or Hyp residues maybe glycosylated. The halogen may be iodo, chloro, fluoro or bromo;preferably iodo for halogen substituted-Tyr and bromo forhalogen-substituted Trp. The Tyr residues may also be substituted withthe 3-hydroxyl or 2-hydroxylisomers (meta-Tyr or ortho-Tyr,respectively) and corresponding O-sulpho- and O-phospho-derivatives. Theacidic amino acid residues may be substituted with any synthetic acidicamino acid, e.g., tetrazolyl derivatives of Gly and Ala. The Leu may besubstituted with Leu (D). The Glu residues may be substituted with Glaor Asp. The Gla residues may be substituted with Glu or Asp. The acidicamino acid residues may be substituted with any synthetic acidic aminoacid, e.g. tetrazolyl derivatives of Gly and Ala. The N-terminal Gln maybe substituted with pyro-glutamate (Z). The aliphatic amino acids may besubstituted by synthetic derivatives bearing non-natural aliphaticbranched or linear side chains C_(n)H_(2n+2) up to and including n=8.The Met residues may be substituted with nor-leucine (Nle). The Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L). Basic residues in the backbonemay be D or L configuration. The central Trp residue within thebeta-turn is preferably epimerized to the D-form.

[0015] Examples of synthetic aromatic amino acid include, but are notlimited to, nitro-Phe, 4-substituted-Phe wherein the substituent isC₁-C₃ alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, —CHO,—CN, —SO₃H and —NHAc. Examples of synthetic hydroxy containing aminoacid, include, but are not limited to, such as 4-hydroxymethyl-Phe,4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr. Examples ofsynthetic basic amino acids include, but are not limited to,N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala,2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala. These andother synthetic basic amino acids, synthetic hydroxy containing aminoacids or synthetic aromatic amino acids are described in Building BlockIndex, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containingamino acids and aromatic amino acids and pages 66-87 for basic aminoacids; see also web address amino-acids. com), incorporated herein byreference, by and available from RSP Amino Acid Analogues, Inc.,Worcester, Mass. Examples of synthetic acid amino acids include thosederivatives bearing acidic functionality, including carboxyl, phosphate,sulfonate and synthetic tetrazolyl derivatives such as described byOrnstein et al. (1993) and in U.S. Pat. No. 5,331,001, each incorporatedherein by reference, and such as shown in the following schemes 1-3.

[0016] Additional derivatives are peptides in which the Asn residues maybe modified to contain an N-glycan and the Ser, Thr and Hyp residues maybe modified to contain an O-glycan (e.g., g-N, g-S, g-T and g-Hyp). Inaccordance with the present invention, a glycan shall mean any N-, S- orO-linked mono-, di-, tri-, poly- or oligosaccharide that can be attachedto any hydroxy, amino or thiol group of natural or modified amino acidsby synthetic or enzymatic methodologies known in the art. Themonosaccharides making up the glycan can include D-allose, D-altrose,D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose,D-galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc),D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose. Thesesaccharides may be structurally modified, e.g., with one or moreO-sulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid,including combinations thereof. The gylcan may also include similarpolyhydroxy groups, such as D-penicillamine 2,5 and halogenatedderivatives thereof or polypropylene glycol derivatives. The glycosidiclinkage is beta and 1-4 or 1-3, preferably 1-3. The linkage between theglycan and the amino acid may be alpha or beta, preferably alpha and is1-.

[0017] Core O-glycans have been described by Van de Steen et al. (1998),incorporated herein by reference. Mucin type O-linked oligosaccharidesare attached to Ser or Thr (or other hydroxylated residues of thepresent peptides) by a GalNAc residue. The monosaccharide buildingblocks and the linkage attached to this first GalNAc residue define the“core glycans,” of which eight have been identified. The type ofglycosidic linkage (orientation and connectivities) are defined for eachcore glycan. Suitable glycans and glycan analogs are described furtherin U.S. Ser. No. 09/420,797 filed 19 Oct. 1999 (now U.S. Pat. No.6,369,193) and in PCT Application No. PCT/US99/24380 filed 19 Oct. 1999(PCT Published Application No. WO 00/23092), each incorporated herein byreference. A preferred glycan is Gal(β1→3)GalNAc(α1→).

[0018] Derivatives also include peptides in which pairs of Cys residuesmay be replaced pairwise with isosteric lactam or ester-thioetherreplacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu orAsp) or Cys/Ala combinations. Sequential coupling by known methods(Barnay et al., 2000; Hruby et al., 1994; Bitan et al., 1997) allowsreplacement of native Cys bridges with lactam bridges. Thioether analogsmay be readily synthesized using halo-Ala residues commerciallyavailable from RSP Amino Acid Analogues. In addition, individual Cysresidues may be replaced with homoCys, seleno-Cys or penicillamine, sothat disulfide bridges may be formed between Cys-homoCys orCys-penicillamine, or homoCys-penicllamine and the like.

[0019] Derivatives and analogs also include truncations of the peptidesdisclosed herein. As used herein “truncations” are used to refer topeptides in which the sequence has been shortened from the matureconotoxin sequence that is predicted by the prepropeptide cleavage sitewith significant retention of activity of the native conotoxin. Thesetruncations can be shortened from the N-terminus, the C-terminus, orboth. As used herein significant retention of activity is used to referto an activity of the truncated conotoxin which is less that 100-foldloss of activity and specificity.

[0020] Derivatives also include radiometal and chelated anti-tumorpeptides. The incorporation of the radiometal eg ^(99m)Tc, ¹¹¹In, ⁹⁰Y,¹⁸⁸Re, 105RhS₄, ¹⁸⁸Re-tisuccin, ⁸⁹Sr, ¹⁵³Sm, ¹⁸⁶Re, ⁶⁷Ga, ²¹¹At, ²¹²Bi,²¹³Bi, ¹⁷⁷Lu, ⁶⁷Cu, ⁶⁴Cu, ¹⁰⁵Rh, ⁴⁷Sc, ¹⁰⁹Pd] in to the conotoxingenerally involves use of a chelate, specific to the particular metal,and a linker group to covalently attach the chelate to the conotoxin[the bifunctional chelate approach]. The design of useful chelates isdependent on the coordination requirements of the specific radiometal.DTPA, DOTA, P₂S₂—COOH BFCA requirement for kinetic TETA, NOTA are commonegs. The requirement for kinetic stability of the metal complex is oftenachieved through the use of multidentate chelate ligands with afunctionalised arm for covalent bonding to some part of the conotoxin iethe amino lysine group. Hence, the conotoxins of the present inventionmay be tagged to produce radiopharmaceuticals. In relation toradioligand probes of β-conotoxins for screening of small molecules,acting at unique allosteric sites, synthesis of such screening tools isnot restricted to radioiodinated tyrosine derivatives. Incorporation ofstandard commercially available tritiated amino acid residues can alsobe utilized.

[0021] The present invention is further directed to a method of treatingdisorders associated with voltage-gated ion channels, ligand-gated ionchannels and/or receptor disorders in a subject comprising administeringto the subject an effective amount of the pharmaceutical compositioncomprising a therapeutically effective amount of a conotoxin peptidedescribed herein or a pharmaceutically acceptable salt or solvatethereof. The present invention is also directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a conotoxinpeptide described herein or a pharmaceutically acceptable salt orsolvate thereof and a pharmaceutically acceptable carrier.

[0022] More specifically, the present invention is also directed tonucleic acids which encode conotoxin peptides of the present inventionor which encodes precursor peptides for these conotoxin peptides, aswell as the precursor peptide. The nucleic acid sequences encoding theprecursor peptides of other conotoxin peptides of the present inventionare set forth in Table 1. Table 1 also sets forth the amino acidsequences of these precursor peptides.

[0023] Another embodiment of the invention contemplates a method ofidentifying compounds that mimic the therapeutic activity of the instantpeptide, comprising the steps of: (a) conducting a biological assay on atest compound to determine the therapeutic activity; and (b) comparingthe results obtained from the biological assay of the test compound tothe results obtained from the biological assay of the peptide.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0024] The present invention is directed to β-superfamily conotoxinpeptides (also referred to as β-conotoxins), derivatives orpharmaceutically acceptable salts thereof. The present invention isfurther directed to the use of this peptide, derivatives thereof andpharmaceutically acceptable salts thereof for the treatment of disordersassociated with voltage-gated ion channels, ligand-gated ion channelsand/or receptors, such as G-protein coupled receptors (GPCRs). Theinvention is further directed to nucleic acid sequences encoding theβ-superfamily conotoxin peptides and encoding propeptides, as well asthe propeptides.

[0025] The present invention, in another aspect, relates to apharmaceutical composition comprising an effective amount of aβ-superfamily conotoxin peptide, a mutein thereof, an analog thereof, aderivative thereof, an active fragment thereof or pharmaceuticallyacceptable salts or solvates. Such a pharmaceutical composition has thecapability of acting at voltage-gated ion channels, ligand-gated ionchannels and/or receptors (such as G-protein coupled receptors (GPCRs)),and are thus useful for treating a disorder or disease of a livinganimal body, including a human, which disorder or disease is responsiveto the partial or complete blockade of such channels or receptorscomprising the step of administering to such a living animal body,including a human, in need thereof a therapeutically effective amount ofa pharmaceutical composition of the present invention.

[0026] G-protein-coupled receptors (GPCRs) are a large, upwards of 1000,and functionally diverse protein superfamily, which form a seventransmembrane (TM) helices bundle with alternating extra-cellular andintracellular loops. GPCRs are considered to be one of the mostimportant groups of drug targets because they are involved in a broadrange of body functions and processes and are related to major diseases.Over the last decades distinct members of the G Protein-Coupled Receptor(GPCR) family emerged as prominent drug targets within pharmaceuticalresearch, since approximately 60% of marketed prescription drugs act byselectively addressing representatives of that class of transmembranesignal transduction systems. It is noteworthy that the majority ofGPCR-targeted drugs elicit their biological activity by selectiveagonism or antagonism of biogenic monoamine receptors, while thedevelopment status of peptide-binding GPCR-addressing compounds is stillin its infancy.

[0027] The β-conotoxins may function as allosteric modulators (i.e.,agonists, partial agonists, neutral antagonists, inverse agonists) ofGPCRs including, but not limited to, sst (sst₁, sst₂, sst₃, sst_(2a),sst_(2b), sst₄, sst₅), cortistatin (CST), melanocortin (MC_(x)R, whereinx=1, 2, 3, 4, 5), opioid (μ, δ, κ), neurokinin (NK₁, NK₂, NK₃),bradykinin (B₁, B₂), galanin (Gal₁, Gal₂, Gal₃), CCK_(A), CCK_(B),endothelin, serotonin, adrenergic receptors, angiotensin (AT₁, AT₂),neuropeptide-Y, sigma1, sigrna2, oxytocin, CGRP, GRPR, histamine,imidazoline, neurotensin (NT₁, NT₂, NT₃), VIP, vasopressin (V1a, V1b,V2), substance K, chemokine receptors (CXCR₁, CXCR₂, CXCR₃, CXCR₄,CXCR₅, CCR₁, CCR_(2b), CCR₃, CCR₄, CCR₅, CCR₆, CCR₇, CCR₈, CX₃CR₁),CRF₁, CRF_(2a), CRF_(2b), CRF_(2g), CRF-BP orexin (Ox₁, Ox₂), urotensin(UT-II), glycoprotein IIb/IIIa, thrombin receptors, orphan GPCRs (eg.MCH₂R/SLT, SP1999/P₂Y₁₂, CRTH₂, NPFF₁, NPFF₂, HH₄R, h-GPR₅₄, CysLT₂,neuromedin receptors, BLTR₂, G₂A, TA₁, LTB₄, ghrelin, motilin MTL-R,purinergic receptors, muscarinic receptors, ORL-1, apelin, CB₁, CB₂ andthe like). For an extensive list of GPCRs see web address gpcr.org/7tm/htmls/entries.html. For additional orphan GPCR references seeShaaban (2001) and Civelli et. al. (2001). This beta turn toxin templatemay also be used to characterize new functional allosteric sites onknown GPCRs. Radiolabelled dervatives serve as screening tools for suchsites and will allow for identification of new small moleculemodulators. The reverse beta turn motif serves as a template for betaturn peptidomimetic design in which the turn template contains the conesnail WK recognition “fingerprint”, examples of such templates can befound in Golebiowski et al. (2001), Horwell (1996) and Beeley (2000).

[0028] Somatostatin Receptors (SSTRs): Somatostatin (SRIF), was firstidentified as a peptide that inhibits growth hormone release. Later itwas shown to have other physiological activities, including theinhibition of the release of many endocrine secretions such asprolactin, TSH and insulin. The peptide also exhibits neuromodulatoryfunctions and may act as a neurotransmitter. Somatostatin has two majoractions; inhibition of hormone and cytokine (IFN-γ, IL-6, IL-8, IL-1)release and inhibition of cellular proliferation. SRIF can inhibit therelease of hormones in the brain and almost all hormone release in thegut, together with many cytokines and growth factors eg PDGF. SRIF canbe produced in cells from neuroendocrine and immune systems. It isproduced in two forms SRIF-28 and SRIF-14. Additionally a novel SST-likepeptide called cortistatin (CST) has been isolated from human. CST-14shares 11 of the 14 amino acids with SRIF. One measurable differencebetween SRIF and CST is that SRIF increases the duration of REM sleep inrats whereas CST decreases it. It is thus possible to postulate thatspecific CST receptors exist.

[0029] Five sst receptors have been identified sst1, 2, 3, 4, 5. All areGPCRs and are encoded on a different chromosome. Both SRIF-14 andSRIF-28 bind to all receptors but SRIF-28 has higher affinity for sst₅.It must be noted that 2 isoforms of sst₂ exist namely, SSt2A and SSt2B.SRIF receptors are widely expressed. Cells from the CNS, gut, pancreas,kidney, thyroid, lung and the immune system express the receptors invarying proportions.

[0030] Overproduction of growth factors from tumours can result insystemic effects, as seen in acromegaly, a chronic debilitating diseasecaused by excessive production of GH. SRIF analogs suppress the releaseof GH and thus can benefit patients. A majority of tumours originatingfrom tissues naturally targeted by SRIF express sst receptors at highlevels.

[0031] Synthetic peptides such as, lanreotide, octreotide and vapreotidebind sst₂ and 5 with high affinity and sst₃ to a lesser extent. Not onlyhave peptide analogs of SRIF been used to reduce tumour growth directlythrough somatostatin receptor signalling but also medicine findsconsiderable use for somatostatin receptors in tumour detection andimaging and now in tumour targeting (Slooter et al., 2001).

[0032] The high level expression of somatostatin receptors (SSTR) onvarious tumor cells has provided the molecular basis for successful useof radiolabeled octreotide/lanreotide analogs as tumor tracers innuclear medicine, similar chemical; modifications of conotoxins bT2,bM1, bG1 may be achieved. The vast majority of human tumors seem tooverexpress the one or the other of five distinct h-SSTR sub-typereceptors. Whereas neuroendocrine tumors frequently overexpress h-SSTR₂,intestinal adenocarcinomas seem to over-express more often h-SSTR₃ orh-SSTR₄, or both of these h-SSTR. In contrast to¹¹¹In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to h-SSTR₂ and 5with high affinity (Kd 0.1-5 nM), to h-SSTR₃ with moderate affinity (Kd10-100 nM) and does not bind to h-SSTR₁ and h-SSTR₄,¹¹¹In/⁹⁰Y-DOTA-lanreotide was found to bind to h-SSTR_(2, 3, 4), and 5with high affinity, and to h-SSTR₁ with lower affinity (K_(d) 200 nM).Based on its unique h-SSTR binding profile, ¹¹¹In-DOTA-lanreotide wassuggested to be a potential radioligand for tumor diagnosis, and⁹⁰Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy.As opposed to ¹¹¹In-DTPA-DPhe1-octreotide and¹¹¹In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphicresults were seen in about one third of (neuroendocrine) tumor patientsconcerning both the tumor uptake as well as detection of tumor lesions.On a molecular level, these discrepancies seem to be based on a “higher”high-affinity binding of ¹¹¹In-DOTA-DPhe1-Tyr3-octreotide to h-SSTR₂.Other somatostatin analogs with divergent affinity to the five knownh-SSTR subtype receptors have also found their way into the clinics,including ⁹⁹ mTc-HYNIC-octreotide or ⁹⁹ mTc-depreotide (NEOSPECT;NEOTECT).

[0033] Most of the imaging results are reported for neuroendocrinetumors (octreotide analogs) or non-small cell lung cancer (⁹⁹mTc-depreotide), indicating high diagnostic capability of this type ofreceptor tracers. Consequently to their use as receptor imaging agents,h-SSTR recognizing radioligands have also been implemented forexperimental receptor-targeted radionuclide therapy. The study“MAURITIUS” (MulticenterAnalysis of a Universal Receptor Imaging andTreatment Initiative, a European Study), a Phase IIa study, showed inpatients with a calculated tumor dose>10 Gy/GBq ⁹⁰Y-DOTA-lanreotide, theproof-of-principle for treating tumor patients with receptor imagingagents. Overall treatment results in>60 patients indicated stable tumordisease in roughly 35% of patients and regressive disease in 15% oftumor patients with different tumor entities. No acute or chronic severehematological toxicity, change in renal or liver function parameters dueto ⁹⁰Y-DOTA-lanreotide, was reported. ⁹⁰In-DOTA-DPhe1-Tyr3-octreotidemay show a higher tumor uptake in neuroendocrine tumor lesions and maytherefore provide even better treatment results in tumor patients, butthere is only limited excess to long-term and survival data at present.Besides newer approaches and recent developments of ¹⁸⁸Re-labeledradioligands no clinical results on the treatment response is availableyet. In conclusion, several radioligands have been implemented on thebasis of peptide receptor recognition throughout the last decade. Aplentitude of preclinical data and clinical studies confirm“proof-of-principle” for their use in diagnosis as well as therapy ofcancer patients. However, an optimal radiopeptide formulation does notyet exist for receptor-targeted radionuclide therapy (Virgolini, 2001).

[0034] During the last decade five different subtypes of melanocortinreceptors have been identified and cloned, all of them are possible asnew targets for drugs in the treatment of a number of clinical importantconditions such as inflammatory diseases (MC₁-receptor agonists),MC₃/MC₄-receptors in the treatment of feeding disorder, agonists fortreatment of obesity and antagonists for anorectic conditions.MC₃/MC₄-agonists or also assumed to be useful for treating sexualdysfunction. In the treatment of seborrheic dermatitis the MC₅ receptoris considered as a target. A number of peptide or peptide like ligands,agonists and/or antagonist has been discovered, however, most of themhave a large similarity with the endogenous ligand A-MSH.

[0035] Melanocortins: The major source of melanocortins is thepituitary, where ACTH and β-lipotropin are the main products from theanterior pituitary, and α-MSH and β-lipotropin are major products fromthe intermediate lobe. All melanocortins, i.e. α-Melanocyte stimulatinghormone (α-MSH), β-MSH, γ-MSH and the endogenous opioid β-endorphin, arecleaved from POMC, but β-MSH and β-endorphin emanate from the C-terminalpart of POMC, i.e. the β-lipotropin. γ-MSH is cleaved from theN-terminal part of POMC. While α-MSH is a tri-decapeptideproteolytically cleaved from proopiomelanocortin (POMC) comprising ofthe N-terminal part of ACTH and is considered as the endogenous ligandto the melanocortin receptors.

[0036] β-MSH is found in the hypothalamus, whereas γ-MSH is found indifferent areas of the CNS, adrenal medulla and neurons of theintestine. α-MSH has been demonstrated in the pituitary, but also inother parts of the CNS, as well as in peripheral parts of the body. Onlylow circulating concentrations of α-MSH have been detected in humans innormal situations, whereas the concentration is increased in severaldiseases.

[0037] Melanocortin Receptors MCRs: Melanocortin receptors belong to thefamily of G-protein coupled, 7-TM receptors, and have been identified inseveral tissues of the body. Today, 5 different subtypes of receptors,MC1-5, have been described. The MC₂ receptor binds only ACTH, and ispresent in the adrenal cortex and also in white adipose tissue ofrodents, but not in man or primates. The MC₁, MC₂, MC₃, MC₄ and MC₅receptors are distributed in different areas/organs of the body. The MC₂receptor is not further discussed since it is considered as the ACTHreceptor. Interestingly, the MC₃ receptor is expressed in low abundanceduring fetal life and expression increases to adult levels after birth,as demonstrated in rats. The opposite is true for the MC4 receptor,which is predominant during fetal life. However, both receptors seem tobe important for different physiological functions postnatally.

[0038] The MC receptors and α-MSH are involved in several physiologicalfunctions besides affecting skin pigmentation. They have effects onlearning, memory, behaviour, including sexual behaviour, regeneration inthe neuromuscular system and protection from central nerve injury,cardiovascular functions, feeding and weight homeostasis, fever andimmunomodulation/inflammation, exocrine functions and interact withopioids and dopamine. They are also ascribed effects such as regulationof the release of pituitary and peripheral hormone.

[0039] Examples of voltage-gated ion channels include the voltage-gatedcalcium channel, the voltage-gated sodium channel, the voltage-gatedpotassium channel and the proton-gated ion channel. Examples ofligand-gated channels include the nicotinic ligand-gated ion channel,ligand-gated glutamate (NMDA) channel and the ligand-gated 5HT₃(serotonin) channel. Examples of receptors include the G-proteinreceptors. Activity of ψ-conotoxins is described in U.S. Pat. No.5,969,096 and in Shon et al. (1997). Activity of bromosleeper conotoxinsis described in U.S. Pat. No. 5,889,147 and in Craig et al. (1997).Activity of σ-conotoxins is described in U.S. Pat. No. 5,889,147.Activity of contryphan conotoxins is described in U.S. Pat. No.6,077,934 and in Jimenez et al. (1996). Activity of conopressins isdescribed in Cruz et al. (1987) and in Kruszynski et al. (1990).Activity of y-conotoxins is described in Fainzilber et al. (1998).Activity of γ-conotoxins is described in Jacobsen et al. (1997) and inHopkins et al. (1995). Activity of γ-conotoxins is described in U.S.Ser. No. 09/497,491 (PCT/US00/03021, PCT published application WO00/46371) as an antagonist for acetylcholine receptors and as analgesicagents for the treatment of pain (whether acute or chronic), includingmigraine, chronic pain, and neuropathic pain, without undesirable sideeffects. Activity of contulakins is described in U.S. Ser. No.09/420,797 (now U.S. Pat. No. 6,369,193) (PCT/US99/24380, PCT publishedapplication WO 00/23092). Each of these references is incorporatedherein by reference.

[0040] Since α-conotoxins are antagonists of the 5HT₃ receptor, they arealso useful in treating irritable bowel syndrome (IBS) and visceralpain. Visceral pain is a common experience in health and disease.Chronic visceral hyperalgesia in the absence of detectable organicdisease has been implicated in many common functional bowel disorders(FDB), such as IBS, non-ulcer dyspepsia (NUD) and non-cardiac chest pain(NCCP).

[0041] Pain in IBS cannot be explained by normal perception of abnormalmotility. In the majority of patients, sensory perception itself isabnormal. Most visceral afferent information is part of the reflexactivity of digestion and does not reach concious perception. Increasingevidence suggests that long term changes in the thresholds and gain ofthe visceral afferent pathways are present in patients with FDBs. Thishas been referred to as visceral hyperalgesia (Mayer et al., 1994).

[0042] It has been proposed that FDBs are a result of increasedexcitability of spinal neurones. According to their model, many inputscan result in transient, short term, or life long sensitization ofafferent pathways involved in visceral reflexes and sensations from thegut. The increased sensory input to interneurons and/or dorsal hornneurons in the spinal cord will result in secondary hyperalgesia, inwhich adjacent, undamaged viscera develop sensitivity to normalinnocuous stimuli (allodynia), and central hyperexcitability as aconsequence of changes in the circuitary of the dorsal horn. Thiscentral sensitization may subsequently extend to supraspinal centersalso.

[0043] Altered spinal processing of visceral sensory information canexplain altered sensory thresholds and altered referral patterns, theperception of visceral sensations without stimulation of visceralmechnoreceptors (sensation of incomplete evacuation), and thesymptomatic involvement of multiple sites in the GI tract, includingextra intestinal sites. Increased excitability of dorsal horn neurones,resulting in the recruitment of previously sub-threshold inputs, mayexplain cutaneous allodynia in some patients with IBS, burningsensations referred to different parts of the body, coldhypersensitivity and pain referral to upper and lower extremities.

[0044] A number of compounds have been shown to modulate visceralsensitivity in IBS patients. These include octreotide (sst2; Novartis),the 5-HT₃ antgonists odansetron (Glaxo) and granisetron (SKB) and theperipheral kappa opioid agonist, fedotozine (Jouveinal SA). The 5-HT₃antagonist alosteron (Glaxo), cuurrently in development for IBS, isactive in modifying the perception of colonic distension and gutcompliance in IBS patients. New drugs in development for the treatmentof IBS that are targeted at pain control as well as dysmotility include5-HT₃ and 5-HT₄ receptor antagonists. 5-HT₃ receptors are locatedthroughout the central and peripheral nervous system—their role inmodulating the activity of visceral afferent and enteric neurones hasled to the proposal that 5-HT acts as a sensitizing agent via thesereceptors on visceral afferent neurones. 5-HT₃ receptor antagonists havebeen widely reported to attenuate blood pressure responses to intestinaldistension. 5-HT₃ antagonists in development for IBS include Alosteron(phase III), which is reported to reduce abdominal pain, slow colonictransit and increase colon compliance in IBS patients. Other compoundswith positive effects include the antiemetic Ramosteron (Yamanouchi),Cilansteron (Solvay) and YM-114 (Yamanouchi). An animal model fordysmotility of the GI tract has been described by Maric et al. (1989).

[0045] In addition to the above uses, the peptides of the presentinvention are also useful (i) for treating or diagnosis of cancer,neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor,GI disease, IBS, restinosis, angiogenesis disorder, diabetes mellitus,endocrine tumor, diarrhea, pancreatic disease, prostate tumor, bleeding,apoptosis, inflammation, pain, diabetes, obesity, sexual dysfunction,acromegaly, glaucoma, cardiovascular, diabetic, retinopathy, depression,myocardial infarction, stroke, epilepsy, anorexia, wasting diseases,seborrheic dermatitis, schizophrenia, mood disorders, chemotherapeuticinduced emesis, disorders associated with changes in blood pressure,immune disorders, nerve damage, acne, GI infections, myocardialinfarction, angina, thromboembolism, cardiovascular disease, (ii) astemplates for small molecule design and (iii) as screening tools.

[0046] The superfamily of seven-transmembrane-domain G-protein-coupledreceptors (GPCRs) is the largest and most diverse group of transmembraneproteins involved in signal transduction. Each of the approximately 1000family members found in vertebrates responds to stimuli as diverse ashormones, neurotransmitters, odorants and light, which selectivelyactivate intracellular signaling events mediated by heterotrimeric Gproteins. Because GPCRs are centrally positioned in the plasma membraneto initiate a cascade of cellular responses by diverse extracellularmediators, it is not surprising that modulation of GPCR function hasbeen successful in the development of many marketed therapeutic agents.It has become clear that GPCRs for which a natural activating ligand hasnot yet been identified (orphan GPCRs) might provide a path todiscovering new cellular substances that are important in humanphysiology. The process of ‘de-orphanizing’ these novel proteins hasaccelerated significantly and opened up new avenues for research inhuman physiology and pharmacology.

[0047] In most cases the extent of sequence homology is insufficient toassign these ‘orphan’ receptors to a particular receptor subfamily.Consequently, reverse molecular pharmacological and functional genomicstrategies are being employed to identify the activating ligands of thecloned receptors. Briefly, the reverse molecular pharmacologicalmethodology includes cloning and expression of orphan GPCRs in mammaliancells and screening these cells for a functional response to cognate orsurrogate agonists present in biological extract preparations, peptidelibraries, and complex compound collections. The functional genomicsapproach involves the use of “humanized” yeast cells, where the yeastGPCR transduction system is engineered to permit functional expressionand coupling of human GPCRs to the endogenous signalling machinery. Bothsystems provide an excellent platform for identifying novel receptorligands. Once activating ligands are identified they can be used aspharmacological tools to explore receptor function and relationship todisease.

[0048] The β-superfamily conotoxins can also be used to design a β-turnmimetic of the β-superfamily conotoxins containing a β-turn motif, e.g.,the —CX1X2KX1C— (SEQ ID NO:338) motif where X1 is any amino acid and X2is Trp in the D or L orientation (or halogenated at position 6 of theindole) or the —CPX3RVC— (SEQ ID NO:339) motif where X3 is Phe in the Dor L configuration. Other β-turn motifs are also present in theβ-superfamily conotoxins as evident from the peptide sequences disclosedin Tables 2 and 3. This hairpin turn would be replaced by a non-peptideturn mimetic, preferably an orally available mimetic. The uniquereceptor binding domains contained within the N and C-terminal regionsof the β-superfamily conotoxin would then be attached to the β-turnscaffold, in such a way as to mimic the 3D spatial array within thenative toxin. As an example of the β-turn motif and a β-turn mimetic,see Scheme 4.

[0049] The β-superfamily conotoxins of the present invention are alsouseful for characterizing sites on GPCRs and for identifying novelreceptor ligands for GPCRS, especially orphan GCPRs. For example, theβ-beta turn toxin template may also be used to characterize newfunctional allosteric sites on known GPCRs. Radiolabelled derivativesserve as screening tools for such sites and will allow foridentification of new small molecule modulators. The reverse beta turnmotif serves as a template for beta turn peptidomimetic design in whichthe turn template contains the cone snail WK recognition “fingerprint”,examples of such templates can be found in Golebiowski et al. (2001) andHorwell (2000). In addition, a ligand which binds to an orphan G-proteincoupled receptor (orphan GPCR) can be identified by contacting aβ-superfamily conotoxin with an orphan GPCR and measuring the amount ofbinding of the conotoxin to the orphan GPCR by methods that are wellknown in the art (Murphy et al., 1998). A homology search to identifyother candidate ligands for testing can then be done on the basis of anypeptide which binds to the orphan GPCR. The candidate ligands may bepeptides or peptide mimetics.

[0050] The conotoxin peptides described herein are sufficiently small tobe chemically synthesized. General chemical syntheses for preparing theforegoing conotoxin peptides are described hereinafter. Various ones ofthe conotoxin peptides can also be obtained by isolation andpurification from specific Conus species using the technique describedin U.S. Pat. No. 4,447,356 (Olivera et al., 1984); U.S. Pat. Nos.5,514,774; 5,719,264; and 5,591,821, as well as in PCT publishedapplication WO 98/03189, the disclosures of which are incorporatedherein by reference.

[0051] Although the conotoxin peptides of the present invention can beobtained by purification from cone snails, because the amounts ofconotoxin peptides obtainable from individual snails are very small, thedesired substantially pure conotoxin peptides are best practicallyobtained in commercially valuable amounts by chemical synthesis usingsolid-phase strategy. For example, the yield from a single cone snailmay be about 10 micrograms or less of conotoxin peptides peptide. By“substantially pure” is meant that the peptide is present in thesubstantial absence of other biological molecules of the same type; itis preferably present in an amount of at least about 85% purity andpreferably at least about 95% purity. Chemical synthesis of biologicallyactive conotoxin peptides peptides depends of course upon correctdetermination of the amino acid sequence.

[0052] The conotoxin peptides can also be produced by recombinant DNAtechniques well known in the art. Such techniques are described bySambrook et al. (1989). A gene of interest (i.e., a gene that encodes asuitable conotoxin peptides) can be inserted into a cloning site of asuitable expression vector by using standard techniques. Thesetechniques are well known to those skilled in the art. The expressionvector containing the gene of interest may then be used to transfect thedesired cell line. Standard transfection techniques such as calciumphosphate co-precipitation, DEAE-dextran transfection or electroporationmay be utilized. A wide variety of host/expression vector combinationsmay be used to express a gene encoding a conotoxin peptide of interest.Such combinations are well known to a skilled artisan. The peptidesproduced in this manner are isolated, reduced if necessary, and oxidizedto form the correct disulfide bonds.

[0053] One method of forming disulfide bonds in the conotoxin peptidesof the present invention is the air oxidation of the linear peptides forprolonged periods under cold room temperatures or at room temperature.This procedure results in the creation of a substantial amount of thebioactive, disulfide-linked peptides. The oxidized peptides arefractionated using reverse-phase high performance liquid chromatography(HPLC) or the like, to separate peptides having different linkedconfigurations. Thereafter, either by comparing these fractions with theelution of the native material or by using a simple assay, theparticular fraction having the correct linkage for maximum biologicalpotency is easily determined. However, because of the dilution resultingfrom the presence of other fractions of less biopotency, a somewhathigher dosage may be required.

[0054] The peptides are synthesized by a suitable method, such as byexclusively solid-phase techniques, by partial solid-phase techniques,by fragment condensation or by classical solution couplings.

[0055] In conventional solution phase peptide synthesis, the peptidechain can be prepared by a series of coupling reactions in whichconstituent amino acids are added to the growing peptide chain in thedesired sequence. Use of various coupling reagents, e.g.,dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole, variousactive esters, e.g., esters of N-hydroxyphthalimide orN-hydroxy-succinimide, and the various cleavage reagents, to carry outreaction in solution, with subsequent isolation and purification ofintermediates, is well known classical peptide methodology. Classicalsolution synthesis is described in detail in the treatise, “Methoden derOrganischen Chemie (Houben-Weyl): Synthese von Peptiden,” (1974).Techniques of exclusively solid-phase synthesis are set forth in thetextbook, “Solid-Phase Peptide Synthesis,” (Stewart and Young, 1969),and are exemplified by the disclosure of U.S. Pat. No. 4,105,603 (Valeet al., 1978). The fragment condensation method of synthesis isexemplified in U.S. Pat. No. 3,972,859 (1976). Other available synthesesare exemplified by U.S. Pat. No. 3,842,067 (1974) and U.S. Pat. No.3,862,925 (1975). The synthesis of peptides containing γ-carboxyglutamicacid residues is exemplified by Rivier et al. (1987), Nishiuchi et al.(1993) and Zhou et al. (1996).

[0056] Common to such chemical syntheses is the protection of the labileside chain groups of the various amino acid moieties with suitableprotecting groups which will prevent a chemical reaction from occurringat that site until the group is ultimately removed. Usually also commonis the protection of an α-amino group on an amino acid or a fragmentwhile that entity reacts at the carboxyl group, followed by theselective removal of the α-amino protecting group to allow subsequentreaction to take place at that location. Accordingly, it is common that,as a step in such a synthesis, an intermediate compound is producedwhich includes each of the amino acid residues located in its desiredsequence in the peptide chain with appropriate side-chain protectinggroups linked to various ones of the residues having labile side chains.

[0057] As far as the selection of a side chain amino protecting group isconcerned, generally one is chosen which is not removed duringdeprotection of the α-amino groups during the synthesis. However, forsome amino acids, e.g., His, protection is not generally necessary. Inselecting a particular side chain protecting group to be used in thesynthesis of the peptides, the following general rules are followed: (a)the protecting group preferably retains its protecting properties and isnot split off under coupling conditions, (b) the protecting group shouldbe stable under the reaction conditions selected for removing theα-amino protecting group at each step of the synthesis, and (c) the sidechain protecting group must be removable, upon the completion of thesynthesis containing the desired amino acid sequence, under reactionconditions that will not undesirably alter the peptide chain.

[0058] It should be possible to prepare many, or even all, of thesepeptides using recombinant DNA technology. However, when peptides arenot so prepared, they are preferably prepared using the Merrifieldsolid-phase synthesis, although other equivalent chemical synthesesknown in the art can also be used as previously mentioned. Solid-phasesynthesis is commenced from the C-terminus of the peptide by coupling aprotected α-amino acid to a suitable resin. Such a starting material canbe prepared by attaching an α-amino-protected amino acid by an esterlinkage to a chloromethylated resin or a hydroxymethyl resin, or by anamide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine(MBHA) resin. Preparation of the hydroxymethyl resin is described byBodansky et al. (1966). Chloromethylated resins are commerciallyavailable from Bio Rad Laboratories (Richmond, Calif.) and from Lab.Systems, Inc. The preparation of such a resin is described by Stewartand Young (1969). BHA and MBHA resin supports are commerciallyavailable, and are generally used when the desired polypeptide beingsynthesized has an unsubstituted amide at the C-terminus. Thus, solidresin supports may be any of those known in the art, such as one havingthe formulae —O—CH₂-resin support, —NH BHA resin support, or —NH-MBHAresin support. When the unsubstituted amide is desired, use of a BHA orMBHA resin is preferred, because cleavage directly gives the amide. Incase the N-methyl amide is desired, it can be generated from an N-methylBHA resin. Should other substituted amides be desired, the teaching ofU.S. Pat. No. 4,569,967 (Kornreich et al., 1986) can be used, or shouldstill other groups than the free acid be desired at the C-terminus, itmay be preferable to synthesize the peptide using classical methods asset forth in the Houben-Weyl text (1974).

[0059] The C-terminal amino acid, protected by Boc or Fmoc and by aside-chain protecting group, if appropriate, can be first coupled to achloromethylated resin according to the procedure set forth in K. Horikiet al. (1978), using KF in DMF at about 60° C. for 24 hours withstirring, when a peptide having free acid at the C-terminus is to besynthesized. Following the coupling of the BOC-protected amino acid tothe resin support, the α-amino protecting group is removed, as by usingtrifluoroacetic acid (TFA) in methylene chloride or TFA alone. Thedeprotection is carried out at a temperature between about 0° C. androom temperature. Other standard cleaving reagents, such as HCl indioxane, and conditions for removal of specific α-amino protectinggroups may be used as described in Schroder & Lubke (1965).

[0060] After removal of the α-amino-protecting group, the remainingα-amino- and side chain-protected amino acids are coupled step-wise inthe desired order to obtain the intermediate compound definedhereinbefore, or as an alternative to adding each amino acid separatelyin the synthesis, some of them may be coupled to one another prior toaddition to the solid phase reactor. Selection of an appropriatecoupling reagent is within the skill of the art. Particularly suitableas a coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU,HATU, TBTU in the presence of HoBt or HoAt).

[0061] The activating reagents used in the solid phase synthesis of thepeptides are well known in the peptide art. Examples of suitableactivating reagents are carbodiimides, such asN,N′-diisopropylcarbodiimide andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide. Other activatingreagents and their use in peptide coupling are described by Schroder &Lubke (1965) and Kapoor (1970).

[0062] Each protected amino acid or amino acid sequence is introducedinto the solid-phase reactor in about a twofold or more excess, and thecoupling may be carried out in a medium of dimethylformamide(DMF):CH₂Cl₂ (1:1) or in DMF or CH₂Cl₂ alone. In cases whereintermediate coupling occurs, the coupling procedure is repeated beforeremoval of the α-amino protecting group prior to the coupling of thenext amino acid. The success of the coupling reaction at each stage ofthe synthesis, if performed manually, is preferably monitored by theninhydrin reaction, as described by Kaiser et al. (1970). Couplingreactions can be performed automatically, as on a Beckman 990 automaticsynthesizer, using a program such as that reported in Rivier et al.(1978).

[0063] After the desired amino acid sequence has been completed, theintermediate peptide can be removed from the resin support by treatmentwith a reagent, such as liquid hydrogen fluoride or TFA (if using Fmocchemistry), which not only cleaves the peptide from the resin but alsocleaves all remaining side chain protecting groups and also the aminoprotecting group at the N-terminus if it was not previously removed toobtain the peptide in the form of the free acid. If Met is present inthe sequence, the Boc protecting group is preferably first removed usingtrifluoroacetic acid (TFA)/ethanedithiol prior to cleaving the peptidefrom the resin with HF to eliminate potential S-alkylation. When usinghydrogen fluoride or TFA for cleaving, one or more scavengers such asanisole, cresol, dimethyl sulfide and methylethyl sulfide are includedin the reaction vessel.

[0064] Cyclization of the linear peptide is preferably affected, asopposed to cyclizing the peptide while a part of the peptido-resin, tocreate bonds between Cys residues. To effect such a disulfide cyclizinglinkage, fully protected peptide can be cleaved from a hydroxymethylatedresin or a chloromethylated resin support by ammonolysis, as is wellknown in the art, to yield the fully protected amide intermediate, whichis thereafter suitably cyclized and deprotected. Alternatively,deprotection, as well as cleavage of the peptide from the above resinsor a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), cantake place at 0° C. with hydrofluoric acid (HF) or TFA, followed byoxidation as described above.

[0065] The peptides are also synthesized using an automatic synthesizer.Amino acids are sequentially coupled to an MBHA Rink resin (typically100 mg of resin) beginning at the C-terminus using an Advanced Chemtech357 Automatic Peptide Synthesizer. Couplings are carried out using1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) and diethylisopropylethylamine (DIEA). The FMOC protecting groupis removed by treatment with a 20% solution of piperidine indimethylformamide(DMF). Resins are subsequently washed with DMF (twice),followed by methanol and NMP.

[0066] Muteins, analogs or active fragments, of the foregoing conotoxinpeptides are also contemplated here. See, e.g., Hammerland et al.(1992). Derivative muteins, analogs or active fragments of the conotoxinpeptides may be synthesized according to known techniques, includingconservative amino acid substitutions, such as outlined in U.S. Pat. No.5,545,723 (see particularly col. 2, line 50—col. 3, line 8); U.S. Pat.No. 5,534,615 (see particularly col. 19, line 45—col. 22, line 33); andU.S. Pat. No. 5,364,769 (see particularly col. 4, line 55—col. 7, line26), each herein incorporated by reference.

[0067] Radiolabeled peptides have been used to show that perhaps onlythe amino acid sequence actually involved in binding to the receptor isessential for achieving tumor uptake. ¹¹¹In-radiolabelled octreotide,which is used to image somatostatin positive tumors, is a prime exampleof this. In addition, advances in tumor biology have demonstratedmetabolic pathways to deliver the nuclide within the cell cytoplasmthrough internalization mechanisms. Some classes of tumors have beenshown to overexpress certain receptors, e.g., glutamate, AMPA, NMDA,somatostatin, melanocortin and the like, and whenever these substancescan be radiolabeled and introduced to the system, they can become thelethal magic bullet by working inside the cell.

[0068] Specificity is the paramount goal in radionuclide therapy becausewith specificity comes safety and efficacy. The strategy in biologicallytargeted therapy is to chemically package the radionuclide to takeadvantage of metabolic pathways or tumor characteristics so that theradionuclide is localized in the target organ or tissue while thenuclear energy is discharged with minimal exposure to healthy tissue.The concentration differential of the therapeutic radio-pharmaceuticalmust be orders of magnitude between target and non-target tissues.Radiation doses of 4000-6000 rads are desirable in the target tissue,while only a few tens of radiation units can be functionally toleratedby some radiosensitive tissues. The short range of the emitted particlesin the tissues makes them very damaging over the range in which theirdecay energy is deposited. The specificity of certain of theβ-superfamily conotoxins for the somatostatin receptor provide thenecessary specificity for the treatment and diagnosis of tumors.

[0069] Where the aim is to provide an image of the tumor, one willdesire to use a diagnostic agent that is detectable upon imaging, suchas a paramagnetic, radioactive or fluorogenic agent. Many diagnosticagents are known in the art to be useful for imaging purposes, as aremethods for their attachment to peptides (see, e.g., U.S. Pat. Nos.5,021,236 and 4,472,509, both incorporated herein by reference). In thecase of paramagnetic ions, one might mention by way of example ions suchas chromium (III), manganese (II), iron (III), iron (II), cobalt (II),nickel (II), copper (II), neodymium (III), samarium (III), ytterbium(III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III),holmium (III) and erbium (III), with gadolinium being particularlypreferred. Ions useful in other contexts, such as X-ray imaging, includebut are not limited to lanthanum (III), gold (III), lead (II), andespecially bismuth (III). Moreover, in the case of radioactive isotopesfor therapeutic and/or diagnostic application, one might mention ¹³¹iodine, ¹²³iodine, ^(99m)technicium, ¹¹¹indium, ¹⁸⁸rhenium, ¹⁸⁶rhenium,⁶⁷gallium, ⁶⁷copper, ⁹⁰yttrium, ¹²⁵iodine, or ²¹¹astatine. Short-livedpositron emission tomography (PET) isotopes, such as ¹⁸flourine, canalso be used for labeling peptides for use in tumor diagnosis (Okarvi,2001).

[0070] Where the aim is to treat the tumor, one will desire to use aradionuclide that will irradiate the tumor. Suitable radionuclidesinclude ¹³¹iodine, ¹²³iodine, ^(99m)technicium, ¹¹¹indium, ¹⁸⁸rhenium,¹⁸⁶rhenium, ⁶⁷gallium, ⁹⁰yttrium, ¹⁰⁵rhodium, ⁸⁹strontium, ¹⁵³samarium,²¹¹astatine, ²¹²bismuth, ²¹³bismuth, ¹⁷⁷lutetium, ⁶⁷copper, ⁴⁷scandium,¹⁰⁹palladium. Optimally, radionuclides are chosen for the specificapplication on the basis of physical and chemical properties such that(a) their decay mode and emitted energy are matched to the deliverysite, (b) their half life and chemical properties are complementary tothe biological processing and (c) production methods can yield theradionuclide at the necessary level of specific activity andradionuclide purity.

[0071] The incorporation of the radiometal into the P-superfamilyconotoxins generally involves use of a chelate, specific to theparticular metal, and a linker group to covalently attach the chelate tothe conotoxin, i.e., a the bifunctional chelate approach. The design ofuseful chelates is dependent on the coordination requirements of thespecific radiometal. DTPA, DOTA, P₂S₂—COOH BFCA requirement for kineticTETA, NOTA are common examples. The requirement for kinetic stability ofthe metal complex is often achieved through the use of multidentatechelate ligands with a functionalized arm for covalent bonding to somepart of the conantokin or γ-carboxyglutamate containing conopeptide,i.e., the lysine amino group. Techniques for chelating radioonuclideswith proteins are well known in the art, such as demonstrated byinterantional patent application publication No. WO 91/01144,incorporated herein by reference.

[0072] In some embodiments, the β-superfamily conotoxins are used incombination with one or more potentiators and/or chemotherapeutic agentsfor the treatment of cancer or tumors. An exemplary potentiator istriprolidine (U.S. Pat. No. 5,114,951) or its cis-isomer which are usedin combination with chemotherapeutic agents. Another potentiator isprocodazole, which is a non-specific immunoprotective agent activeagainst viral and bacterial infections. Other potentiators which can beused with conantokins or γ-carboxyglutamate containing peptides andoptionally another chemotherapeutic agent to treat or inhibit the growthof cancer include monensin, an anti-sense inhibitor of the RAD51 gene,bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, ananti-transferrin receptor immunotoxin, metoclopramide,7-thia-8-oxoguanosine,N-solanesyl-N,N′-bis(3,4-dimethoxybenzyl)ethylene-diamine, leucovorin,heparin, N-[4-[(4-fluorphenyl)sulfonly]phenyl] acetamide, heparinsulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxiccell cytotoxic agent, muramyl dipeptide, vitamin A, 2′-deoxycoformycin,a bis-diketopiperazine derivative, and dimethyl sulfoxide.

[0073] The chemotherapeutic agents which can be used with conantokins orγ-carboxyglutamate containing peptides and an optional potentiator aregenerally grouped as DNA-interactive agents, antimetabolites,tubulin-interactive agents, hormonal agents and others such asasparaginase or hydroxyurea. Each of the groups of chemotherapeuticagents can be further divided by type of activity or compound. Thechemotherapeutic agents used in combination with y-carboxy-glutamatecontaining peptides include members of all of these groups. For adetailed discussion of chemotherapeutic agents and their method ofadministration, see Dorr et al. (1994) and U.S. Pat. No. 6,290,929.

[0074] DNA-interactive agents include the alkylating agents, e.g.cisplatin, cyclophosphamide, altretamine; the DNA strand-breakageagents, such as bleomycin; the intercalating topoisomerase IIinhibitors, e.g., dactinomycin and doxorubicin; the nonintercalatingtopoisomerase II inhibitors such as, etoposide and teniposde; and theDNA minor groove binder plicamydin. The alkylating agents form covalentchemical adducts with cellular DNA, RNA, and protein molecules and withsmaller amino acids, glutathione and similar chemicals. Generally, thesealkylating agents react with a nucleophilic atom in a cellularconstituent, such as an amino, carboxyl, phosphate, sulfhydryl group innucleic acids, proteins, amino acids, or glutathione.

[0075] The antimetabolites interfere with the production of nucleicacids by one or the other of two major mechanisms. Some of the drugsinhibit production of the deoxyribonucleoside triphosphates that are theimmediate precursors for DNA synthesis, thus inhibiting DNA replication.Some of the compounds are sufficiently like purines or pyrimidines to beable to substitute for them in the anabolic nucleotide pathways. Theseanalogs can then be substituted into the DNA and RNA instead of theirnormal counterparts.

[0076] Tubulin interactive agents act by binding to specific sites ontubulin, a protein that polymerizes to form cellular microtubules.Microtubules are critical cell structure units. When the interactiveagents bind on the protein, the cell cannot form microtubules. Tubulininteractive agents include colchicine, vincristine and vinblastine, bothalkaloids and paclitaxel and cytoxan.

[0077] Hormonal agents are also useful in the treatment of cancers andtumors. They are used in hormonally susceptible tumors and are usuallyderived from natural sources. These include: estrogens, conjugatedestrogens and ethinyl estradiol and diethylstilbesterol, chlortrianisenand idenestrol; progestins such as hydroxyprogesterone caproate,medroxyprogesterone, and megestrol; and androgens such as testosterone,testosterone propionate; fluoxymesterone, methyltestosterone. Adrenalcorticosteroids are derived from natural adrenal cortisol orhydrocortisone. They are used because of their anti inflammatorybenefits as well as the ability of some to inhibit mitotic divisions andto halt DNA synthesis. These compounds include, prednisone,dexamethasone, methylprednisolone, and prednisolone. Leutinizing hormonereleasing hormone agents or gonadotropin-releasing hormone antagonistsare used primarily the treatment of prostate cancer. These includeleuprolide acetate and goserelin acetate. They prevent the biosynthesisof steroids in the testes. Antihormonal antigens include: antiestrogenicagents such as tamoxifen, antiandrogen agents such as flutamide; andantiadrenal agents such as mitotane and aminoglutethimide.

[0078] Pharmaceutical compositions containing a compound of the presentinvention as the active ingredient can be prepared according toconventional pharmaceutical compounding techniques. See, for example,Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack PublishingCo., Easton, Pa.). Typically, an antagonistic amount of activeingredient will be admixed with a pharmaceutically acceptable carrier.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., intravenous, oral,parenteral or intrathecally. For examples of delivery methods see U.S.Pat. No. 5,844,077, incorporated herein by reference.

[0079] “Pharmaceutical composition” means physically discrete coherentportions suitable for medical administration. “Pharmaceuticalcomposition in dosage unit form” means physically discrete coherentunits suitable for medical administration, each containing a daily doseor a multiple (up to four times) or a sub-multiple (down to a fortieth)of a daily dose of the active compound in association with a carrierand/or enclosed within an envelope. Whether the composition contains adaily dose, or for example, a half, a third or a quarter of a dailydose, will depend on whether the pharmaceutical composition is to beadministered once or, for example, twice, three times or four times aday, respectively.

[0080] The term “salt”, as used herein, denotes acidic and/or basicsalts, formed with inorganic or organic acids and/or bases, preferablybasic salts. While pharmaceutically acceptable salts are preferred,particularly when employing the compounds of the invention asmedicaments, other salts find utility, for example, in processing thesecompounds, or where non-medicament-type uses are contemplated. Salts ofthese compounds may be prepared by art-recognized techniques.

[0081] Examples of such pharmaceutically acceptable salts include, butare not limited to, inorganic and organic addition salts, such ashydrochloride, sulphates, nitrates or phosphates and acetates,trifluoroacetates, propionates, succinates, benzoates, citrates,tartrates, fumarates, maleates, methane-sulfonates, isothionates,theophylline acetates, salicylates, respectively, or the like. Loweralkyl quaternary ammonium salts and the like are suitable, as well.

[0082] As used herein, the term “pharmaceutically acceptable” carriermeans a non-toxic, inert solid, semi-solid liquid filler, diluent,encapsulating material, formulation auxiliary of any type, or simply asterile aqueous medium, such as saline. Some examples of the materialsthat can serve as pharmaceutically acceptable carriers are sugars, suchas lactose, glucose and sucrose, starches such as corn starch and potatostarch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt, gelatin, talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols, such as propyleneglycol, polyols such as glycerin, sorbitol, mannitol and polyethyleneglycol; esters such as ethyl oleate and ethyl laurate, agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcoholand phosphate buffer solutions, as well as other non-toxic compatiblesubstances used in pharmaceutical formulations.

[0083] Wetting agents, emulsifiers and lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. Examples ofpharmaceutically acceptable antioxidants include, but are not limitedto, water soluble antioxidants such as ascorbic acid, cysteinehydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite,and the like; oil soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, aloha-tocopherol and the like; and the metalchelating agents such as citric acid, ethylenediamine tetraacetic acid(EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[0084] For oral administration, the compounds can be formulated intosolid or liquid preparations such as capsules, pills, tablets, lozenges,melts, powders, suspensions or emulsions. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, suspending agents, andthe like in the case of oral liquid preparations (such as, for example,suspensions, elixirs and solutions); or carriers such as starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like in the case of oral solidpreparations (such as, for example, powders, capsules and tablets).Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe sugar-coated or enteric-coated by standard techniques. The activeagent can be encapsulated to make it stable to passage through thegastrointestinal tract while at the same time allowing for passageacross the blood brain barrier. See for example, WO 96/11698.

[0085] For parenteral administration, the compound may be dissolved in apharmaceutical carrier and administered as either a solution or asuspension. Illustrative of suitable carriers are water, saline,dextrose solutions, fructose solutions, ethanol, or oils of animal,vegetative or synthetic origin. The carrier may also contain otheringredients, for example, preservatives, suspending agents, solubilizingagents, buffers and the like. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid.

[0086] A variety of administration routes are available. The particularmode selected will depend of course, upon the particular drug selected,the severity of the disease state being treated and the dosage requiredfor therapeutic efficacy. The methods of this invention, generallyspeaking, may be practiced using any mode of administration that ismedically acceptable, meaning any mode that produces effective levels ofthe active compounds without causing clinically unacceptable adverseeffects. Such modes of administration include oral, rectal, sublingual,topical, nasal, transdermal or parenteral routes. The term “parenteral”includes subcutaneous, intravenous, epidural, irrigation, intramuscular,release pumps, or infusion.

[0087] For example, administration of the active agent according to thisinvention may be achieved using any suitable delivery means, including:

[0088] (a) pump (see, e.g., Luer & Hatton (1993), Zimm et al. (1984) andEttinger et al. (1978));

[0089] (b), microencapsulation (see, e.g., U.S. Pat. Nos. 4,352,883;4,353,888; and 5,084,350);

[0090] (c) continuous release polymer implants (see, e.g., U.S. Pat. No.4,883,666);

[0091] (d) macroencapsulation (see, e.g., U.S. Pat. Nos. 5,284,761,5,158,881, 4,976,859 and 4,968,733 and published PCT patent applicationsWO92/19195, WO 95/05452);

[0092] (e) naked or unencapsulated cell grafts to the CNS (see, e.g.,U.S. Pat. Nos. 5,082,670 and 5,618,531);

[0093] (f) injection, either subcutaneously, intravenously,intra-arterially, intramuscularly, or to other suitable site; or

[0094] (g) oral administration, in capsule, liquid, tablet, pill, orprolonged release formulation.

[0095] In one embodiment of this invention, an active agent is delivereddirectly into the CNS, preferably to the brain ventricles, brainparenchyma, the intrathecal space or other suitable CNS location, mostpreferably intrathecally.

[0096] Alternatively, targeting therapies may be used to deliver theactive agent more specifically to certain types of cell, by the use oftargeting systems such as antibodies or cell specific ligands. Targetingmay be desirable for a variety of reasons, e.g. if the agent isunacceptably toxic, or if it would otherwise require too high a dosage,or if it would not otherwise be able to enter the target cells.

[0097] The active agents, which are peptides, can also be administeredin a cell based delivery system in which a DNA sequence encoding anactive agent is introduced into cells designed for implantation in thebody of the patient, especially in the spinal cord region. Suitabledelivery systems are described in U.S. Pat. No. 5,550,050 and publishedPCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452,WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635.Suitable DNA sequences can be prepared synthetically for each activeagent on the basis of the developed sequences and the known geneticcode.

[0098] Exemplary methods for administering compounds (e.g., so as toachieve sterile or aseptic conditions) will be apparent to the skilledartisan. Certain methods suitable for administering compounds usefulaccording to the present invention are set forth in Goodman and Gilman'sThe Pharmacological Basis of Therapeutics, 7th Ed. (1985). Theadministration to the patient can be intermittent; or at a gradual,continuous, constant or controlled rate. Administration can be to awarm-blooded animal (e.g. a mammal, such as a mouse, rat, cat, rabbit,dog, pig, cow or monkey); but advantageously is administered to a humanbeing. Administration occurs after general anesthesia is administered.The frequency of administration normally is determined by ananesthesiologist, and typically varies from patient to patient.

[0099] The active agent is preferably administered in an therapeuticallyeffective amount. By a “therapeutically effective amount” or simply“effective amount” of an active compound is meant a sufficient amount ofthe compound to treat the desired condition at a reasonable benefit/riskratio applicable to any medical treatment. The actual amountadministered, and the rate and time-course of administration, willdepend on the nature and severity of the condition being treated.Prescription of treatment, e.g. decisions on dosage, timing, etc., iswithin the responsibility of general practitioners or spealists, andtypically takes account of the disorder to be treated, the condition ofthe individual patient, the site of delivery, the method ofadministration and other factors known to practitioners. Examples oftechniques and protocols can be found in Remington 's PharmaceuticalSciences.

[0100] Dosage may be adjusted appropriately to achieve desired levels,locally or systemically, and depending on use as a diagnostic agent or atherapeutic agent. For therapeutic uses, the active agents of thepresent invention typically exhibit their effect at a dosage range fromabout 0.001 mg/kg to about 250 mg/kg, preferably from about 0.01 mg/kgto about 100 mg/kg of the active ingredient, more preferably from a bout0.05 mg/kg to about 75 mg/kg. A suitable dose can be administered inmultiple sub-doses per day. Typically, a dose or sub-dose may containfrom about 0.1 mg to about 500 mg of the active ingredient per unitdosage form. A more preferred dosage will contain from about 0.5 mg toabout 100 mg of active ingredient per unit dosage form. Dosages aregenerally initiated at lower levels and increased until desired effectsare achieved. In the event that the response in a subject isinsufficient at such doses, even higher doses (or effective higher dosesby a different, more localized delivery route) may be employed to theextent that patient tolerance permits. Continuous dosing over, forexample 24 hours or multiple doses per day are contemplated to achieveappropriate systemic levels of compounds.

[0101] For diagnostic uses, an appropriate dosage will depend on thepeptide and the detectable label. A suitable dose to be injected is inthe range to enable imaging by scanning procedures known in the art.When a radiolabeled conantokin is used, it may be administered in a dosehaving a radioactivity of form 0.1 to 50 mCi, preferably, 0.1 to 30 mCiand more preferably, 0.1 to 20 mCi. For therpeutic uses, an appropriatedosage will depend on the peptide, the radionuculide, the size andlocation of the tumor and the half life of the active agent in thetumor. In general, the dose is calculated on the basis of of theradioactivity distribution to each organ and on observed target uptake.For example, the active agent may be administered at a daily dosagerange having a radioactivity of from 0.1 to 3 mCi/kg, preferably 1 to 3mCi/kg, more preferably 1 to 1.5 mCi/kg.

[0102] Advantageously, the compositions are formulated as dosage units,each unit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of dosage forms according to the invention.

[0103] It is only necessary that the active ingredient constitute aneffective amount, i.e., such that a suitable effective dosage will beconsistent with the dosage form employed in single or multiple unitdoses. The exact individual dosages, as well as daily dosages, aredetermined according to standard medical principles under the directionof a physician or veterinarian for use humans or animals.

[0104] The pharmaceutical compositions will generally contain from about0.0001 to 99 wt. %, preferably about 0.001 to 50 wt. %, more preferablyabout 0.01 to 10 wt. % of the active ingredient by weight of the totalcomposition. In addition to the active agent, the pharmaceuticalcompositions and medicaments can also contain other pharmaceuticallyactive compounds. Examples of other pharmaceutically active compoundsinclude, but are not limited to, analgesic agents, cytokines andtherapeutic agents in all of the major areas of clinical medicine. Whenused with other pharmaceutically active compounds, the conopeptides ofthe present invention may be delivered in the form of drug cocktails. Acocktail is a mixture of any one of the compounds useful with thisinvention with another drug or agent. In this embodiment, a commonadministration vehicle (e.g., pill, tablet, implant, pump, injectablesolution, etc.) would contain both the instant composition incombination supplementary potentiating agent. The individual drugs ofthe cocktail are each administered in therapeutically effective amounts.A therapeutically effective amount will be determined by the parametersdescribed above; but, in any event, is that amount which establishes alevel of the drugs in the area of body where the drugs are required fora period of time which is effective in attaining the desired effects.

[0105] The present invention also relates to rational drug design forthe indentification of additional drugs which can be used for thepursposes described herein. The goal of rational drug design is toproduce structural analogs of biologically active polypeptides ofinterest or of small molecules with which they interact (e.g., agonists,antagonists, inhibitors) in order to fashion drugs which are, forexample, more active or stable forms of the polypeptide, or which, e.g.,enhance or interfere with the function of a polypeptide in vivo. Severalapproaches for use in rational drug design include analysis ofthree-dimensional structure, alanine scans, molecular modeling and useof anti-id antibodies. These techniques are well known to those skilledin the art. Such techniques may include providing atomic coordinatesdefining a three-dimensional structure of a protein complex formed bysaid first polypeptide and said second polypeptide, and designing orselecting compounds capable of interfering with the interaction betweena first polypeptide and a second polypeptide based on said atomiccoordinates.

[0106] Following identification of a substance which modulates oraffects polypeptide activity, the substance may be further investigated.Furthermore, it may be manufactured and/or used in preparation, i.e.,manufacture or formulation, or a composition such as a medicament,pharmaceutical composition or drug. These may be administered toindividuals.

[0107] A substance identified as a modulator of polypeptide function maybe peptide or non-peptide in nature. Non-peptide “small molecules” areoften preferred for many in vivo pharmaceutical uses. Accordingly, amimetic or mimic of the substance (particularly if a peptide) may bedesigned for pharmaceutical use.

[0108] The designing of mimetics to a known pharmaceutically activecompound is a known approach to the development of pharmaceuticals basedon a “lead” compound. This approach might be desirable where the activecompound is difficult or expensive to synthesize or where it isunsuitable for a particular method of administration, e.g., purepeptides are unsuitable active agents for oral compositions as they tendto be quickly degraded by proteases in the alimentary canal. Mimeticdesign, synthesis and testing is generally used to avoid randomlyscreening large numbers of molecules for a target property.

[0109] Once the pharmacophore has been found, its structure is modeledaccording to its physical properties, e.g., stereochemistry, bonding,size and/or charge, using data from a range of sources, e.g.,spectroscopic techniques, x-ray diffraction data and NMR. Computationalanalysis, similarity mapping (which models the charge and/or volume of apharmacophore, rather than the bonding between atoms) and othertechniques can be used in this modeling process.

[0110] A template molecule is then selected, onto which chemical groupsthat mimic the pharmacophore can be grafted. The template molecule andthe chemical groups grafted thereon can be conveniently selected so thatthe mimetic is easy to synthesize, is likely to be pharmacologicallyacceptable, and does not degrade in vivo, while retaining the biologicalactivity of the lead compound. Alternatively, where the mimetic ispeptide-based, further stability can be achieved by cyclizing thepeptide, increasing its rigidity. The mimetic or mimetics found by thisapproach can then be screened to see whether they have the targetproperty, or to what extent it is exhibited. Further optimization ormodification can then be carried out to arrive at one or more finalmimetics for in vivo or clinical testing.

[0111] The present invention further relates to the use of a labeled(e.g., radiolabel, fluorophore, chromophore or the like) of theβ-conotoxins described herein as a molecular tool both in vitro and invivo, for discovery of small molecules that exert their action at orpartially at the same functional site as the native toxin and capable ofelucidation similar functional responses as the native toxin. In oneembodiment, the displacement of a labeled β-conotoxin from its receptoror other complex by a candidate drug agent is used to identify suitablecandidate drugs. In a second embodiment, a biological assay on a testcompound to determine the therapeutic activity is conducted and comparedto the results obtained from the biological assay of a β-conotoxin. In athird embodiment, the binding affinity of a small molecule to thereceptor of a β-conotoxin is measured and compared to the bindingaffinity of a β-conotoxin to its receptor.

[0112] In view of the targets of the β-conotoxins, they may be used fortreating the following conditions: cancer (neoplasm, solid tumor,diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS,restinosis, angiogenesis disorder, diabetes mellitus, endocrine tumor,diarrhea, pancreatic disease, prostate tumor, bleeding, apoptosis),inflammation, pain, diabetes, obesity, sexual dysfunction, acromegaly,glaucoma, cardiovascular, diabetic, retinopathy, depression, myocardialinfarction, stroke, epilepsy, anorexia, wasting diseases, seborrheicdermatitis, schizophrenia, mood disorders, chemotherapeutic inducedemesis, disorders associated with changes in blood pressure, immunedisorders, nerve damage, acne, GI infections, myocardial infarction,angina, thromboembolism and cardiovascular disease.

[0113] The practice of the present invention employs, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA, genetics, immunology, cell biology, cellculture and transgenic biology, which are within the skill of the art.See, e.g., Maniatis et al., 1982; Sambrook et al., 1989; Ausubel et al.,1992; Glover, 1985; Anand, 1992; Guthrie and Fink, 1991; Harlow andLane, 1988; Jakoby and Pastan, 1979; Nucleic Acid Hybridization (B. D.Hames & S. J. Higgins eds. 1984); Transcription And Translation (B. D.Hames & S. J. Higgins eds. 1984); Culture Of Animal Cells (R. I.Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRLPress, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984);the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); GeneTransfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds.,1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154and 155 (Wu et al. eds.), Immunochemical Methods In Cell And MolecularBiology (Mayer and Walker, eds., Academic Press, London, 1987); HandbookOf Experimental Immunology, Volumes I-IV (D. M. Weir and C. C.Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition,Blackwell Scientific Publications, Oxford, 1988; Hogan et al.,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986).

EXAMPLES

[0114] The present invention is described by reference to the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below were utilized.

Example 1 Isolation of DNA Encoding β-Superfamily Conopeptides

[0115] DNA coding for β-superfamily conotoxin peptides was isolated andcloned in accordance with conventional techniques using generalprocedures well known in the art, such as described in Olivera et al.(1996), including using primers based on the DNA sequence of knownconotoxin peptides. Alternatively, cDNA libraries was prepared fromConus venom duct using conventional techniques. DNA from single cloneswas amplified by conventional techniques using primers which correspondapproximately to the M13 universal priming site and the M13 reverseuniversal priming site. Clones having a size of approximately 300-500nucleotides were sequenced and screened for similarity in sequence toknown conotoxins. The DNA sequences and encoded propeptide sequences areset forth in Table 1. DNA sequences coding for the mature toxin can alsobe prepared on the basis of the DNA sequences set forth in Table1. Analignment of the conopeptides of the present invention is set forth inTable 2. Sequences of truncated and analog peptides are set forth inTable 3. TABLE 1 Sequences of β-Superfamily Conotoxins Name: Fd14.1Species: flavidus Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:1)CCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATGACTTAACCCCACAGCTTATTTTGCAAAGTCTGGATTCCCGTCGTCATGATCACGGCATTCGTCCGAAGAGAGTCGACATATGTAACTGGAGGATATGTGCACCAAACCCATTGAGACGACATGATCTTAAGAAAGGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGGTTGGATTTGTCCTTGTTTAAGCCGTTGTACTGATGACATCTCTGCACTATGAAATAAAGCTGATGTGACAAACTAAAAAAAAA AAAAAAAATranslation: MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPDDLTPQLILQSLDSRRHDHGIR(SEQ ID NO:2) PKRVDICNWRICAPNPLRRHDLKKGNN Toxin Sequence:His-Asp-His-Gly-Ile-Arg-Xaa3-Lys-Arg-Val-Asp-Ile-Cys- (SEQ ID NO:3)Asn-Xaa4-Arg-Ile-Cys-Ala-Xaa3-Asn-Xaa3-Leu-Arg-Arg-His-Asp-Leu-Lys-Lys-Gly-Asn-Asn-{circumflex over ( )} Name: Mi14.1 Species:miles Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGCTCAC (SEQ ID NO:4)CGTCGGGAGTCACGTCCATCGGTCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGAATGGTGCAGGCAACACCAAGCAACAAGACCAAAGTCCTCATCATGTGTGTTGTGCTATTGGTCCGGTTCTTCCATTCTGTTGTGTCAGTTGGCTGCACAAACTCCATTGAACTGGCCAATGAAAATAACTCAGGAATAGACAGAAAGGCAAAAAAAAAAAAAAAAA Translation:MQTAYWVMVMMMVVGLTVGSHVHRSHSPTSRSHGDDSIHDKTIHQHLFARLPLENN (SEQ ID NO:5)DDHRSVDLPAGNGAGNTKQQDQSPHHVCCAIGPVLPFCCVSWLHKLH Toxin Sequence:Xaa2-Gln-Asp-Gln-Ser-Xaa3-His-His-Val-Cys-Cys-Ala-Ile- (SEQ ID NO:6)Gly-Xaa3-Val-Leu-Xaa3-Phe-Cys-Cys-Val-Ser-Xaa4-Leu-His-Lys-Leu-His-{circumflex over ( )} Name: Mi14.2 Species: miles Isolated:No Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGTTCAC (SEQ ID NO:7)CGTCGGGGGTCACGTCCATCGGTCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCAGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGACTAGCGCAGGCGACATGAAACCACAACGCCAAAGACGTCTCTGCTGCATCTTTGCCCCGATTCTTTGGTTCTGTTGTCACGGTTAACAGCTCAAATTACACTGCACTGGCCGATTGAAAGAACTGCAATAAACGGAAAAAAAAAAAAAAAA Translation:MQTAYWVMVMMMVVGFTVGGHVHRSHSPTSRSHGDDSIHDKTIHQHLFARLPQENN (SEQ ID NO:8)DDHRSVDLPAGTSAGDMKPQRQRRLCCIFAPILWFCCHG Toxin Sequence:Leu-Cys-Cys-Ile-Phe-Ala-Xaa3-Ile-Leu-Xaa4-Phe-Cys-Cys- (SEQ ID NO:9)His-# Name: Cp14.1 Species: capitaneus Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGTTCAC (SEQ ID NO:10)CGTCGGGGGTCACGTCCATCGGTCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCATTCATGACGAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCAGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGACTAGCGCAGGCGACATGAAACCACAACGCCAAAGAGGTTTCTGCTGCGACTTTCCCCCGATTTTTTGGTTCTGTTGTATCGGTTAACAGCACAAATTACACTGCACTGGCCGATTGAAAGAACTGCAA TAAACGGAAAAAAAATranslation: MQTAYWVMVMMMVVGFTVGGHVHRSHSPTSRSHGDDSIHDETIHQHLFARLPQENN(SEQ ID NO:11) DDHRSVDLPAGTSAGDMKPQRQRGFCCDFPPIFWFCCIG Toxin Sequence:Gly-Phe-Cys-Cys-Asp-Phe-Xaa3-Xaa3-Ile-Phe-Xaa4-Phe-Cys- (SEQ ID NO:12)Cys-Ile-# Name: Ge14.1 Species: generalis Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTAATGGTGATGATGATGGTGTGGATTAAAGG (SEQ ID NO:13)CCCTGTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTGACCCCAGTGTTTGCCTTGCATCATCCGGTTTCCCATCGTCGGTCTCACAGCAGTAGTTTGTGGTGTGTATGTCCATTCAGGGTGTGTCCACCATGCCATGGAAGATGACCTGGTCCCAAACCAACAAAATAACGTCAGACAACCGCCACAACTTTAGTACGACATCCCTTAATACGACTTCAGCAAGTATTTTAACATCACTATGGTGTGATGAAATCA GTTGCTTTAAAATranslation: MQTAYWVMVMMMVWIKGPVSEGGKLNDVIRGLVPDDLTPVFALHHPVSHRRSHSSS(SEQ ID NO:14) LWCVCPFRVCPPCHGR Toxin Sequence:Ser-His-Ser-Ser-Ser-Leu-Xaa4-Cys-Val-Cys-Xaa3-Phe-Arg- (SEQ ID NO:15)Val-Cys-Xaa3-Xaa3-Cys-His-# Name: Wi14.1 Species: wittigi Cloned: YesDNA Sequence: ATGATGTTGGTGTGGATTACAGCCCCTCTGCCTGAAGGTGGTAAACTGAAGCACGT(SEQ ID NO:16) AATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTAGTTCTGACGGCAGTGATCCGAAGGCAAAAAAACAGTGTATGTGGAAGAGATGTATACCAGACCAATCGAGACTAGAAGAAGATGAATGATGTCAGACAACCGCCATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCACTGTGGTTCTGAAGACATCAGTTGCTTTAAAAGATTGGATTCTTCCTTGTTTAAGAGTTGTACTGANATCATTCCTGCCCTGTGAAATAAAGCTGATGTTGACNNCAAACAA AAAAAAAAAAAATranslation: MMLVWITAPLPEGGKLKHVIRGLVPDDLTPQLILRSLISRRSSDGSDPKAKKQCMW(SEQ ID NO:17) KRCIPDQSRLEEDE Toxin Sequence:Ser-Ser-Asp-Gly-Ser-Asp-Xaa3-Lys-Ala-Lys-Lys-Gln-Cys- (SEQ ID NO:18)Met-Xaa4-Lys-Arg-Cys-Ile-Xaa3-Asp-Gln-Ser-Arg-Leu-Xaa1-Xaa1-Asp-Xaa1-{circumflex over ( )} Name: Cn14.1 Species: consorsCloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:19)CCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGTCACACATCTTAATCCCACAGCATACCTTGCGAAGTCTGACTTCCCGTGATCGTTCTGACAACGGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATAGAGACGACCACGAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAACTATTTTAACATCACTGTGGTTGTGAAGAAATCAGTCGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACATAAAAAAAAAAAAAAAAAGTACTCT GCGTTGTTACTCGAGTranslation: MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVSHILIPQHTLRSLTSRDRSDNGG(SEQ ID NO:20) SSGAQICIWKVCPPSP Toxin Sequence:Asp-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:21)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-{circumflex over ( )} Name:Cn14.2 Species: consors Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:22)CCCTCTGTCTGAAGGTGGTAAATTGAACGACGCAATTCGGGGTTTGGTGTCACACATCTTAATCCCACAGCATACCTTGCGAAGTCTGACTTCCCGTGCTCGTTCTGACAACGGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACGACCACAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAATAAAAAAGAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDAIRGLVSHILIPQHTLRSLTSRARSDNGG (SEQ ID NO:23)SSGAQICIWKVCPPSPWRRPQGKR Toxin Sequence:Ala-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:24)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg- Xaa3-Gln-# Name:Cn14.3 Species: consors Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:25)CCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACTTCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTAATGGTTCTGGCAGCAGTAATCAGAAAGAAGCACAACTATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAATTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAACCCAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHFLTPQHILQSLTSRNGSGSSN (SEQ ID NO:26)QKEAQLCIWKVCPPSPWR Toxin Sequence:Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:27)Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-{circumflex over( )} Name: T14.1 Species: tulipa Cloned: Yes DNA Sequence:GGATCCATGCAGACGGCCTACTGGGTGATGCTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:28)CCCTCTGTCTGAAGGTGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCACACGTCTTAACCCCACAGCATATCTTGCAAAGTCTGGTTTCCCGTCGTCATTTTAACAGCGTTGTTCCGACGGTATACATATGCATGTGGAAGGTATGTCCACCATCGCCATAGAGACGACCATAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTCAGAGTTGTACTGATATCAGCTCTGCACTATCAAATAAAGCTGAAGTGACAAACCNNAAAAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMLMMMVWITAPLSEGGKLNDVIRGLVPHVLTPQHILQSLVSRRHFNSVV (SEQ ID NO:29)PTVYICMWKVCPPSP Toxin Sequence:His-Phe-Asn-Ser-Val-Val-Xaa3-Thr-Val-Xaa5-Ile-Cys-Met- (SEQ ID NO:30)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-{circumflex over ( )} Name: T14.2Species: tulipa Isolated: No Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGCTGTTGATGATGGTGGGCATTACAGCCCCTCT (SEQ ID NO:31)GCCTGAAGGTGGTAAACCGAACAGCGTAATTCGGGGTTTGGTGCCAAACGACTTAACTCCACAGCATACCTTGCGAAGTCTGATTTCCCGTCGTCAAACTGACGTTCTTCTGGAGGCTACCCTTTTGACAACACCAGCCCCCGAGCAGAGATTGTTCTGCTTCTGGAAGTCATGTTGGCCAAGGCCCTACCCTTGGAGACGACGTGATCTTAATGGAAAACGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCATTAATACGACTTCAGCAAATATTTTAACATTACTGTGGTTGTGAAGAAATCACTTGCTTTAAAAGATTGGTTTTTTCCTTGTTTCAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAAGCTG ATGTranslation: MQTAYWVMLLMMVGITAPLPEGGKPNSVIRGLVPNDLTPQHTLRSLISRRQTDVLL(SEQ ID NO:32) EATLLTTPAPEQRLFCFWKSCWPRPYPWRRRDLNGKR Toxin Sequence:Xaa2-Thr-Asp-Val-Leu-Leu-Xaa1-Ala-Thr-Leu-Leu-Thr-Thr- (SEQ ID NO:33)Xaa3-Ala-Xaa3-Xaa1-Gln-Arg-Leu-Phe-Cys-Phe-Xaa4-Lys-Ser-Cys-Xaa4-Xaa3-Arg-Xaa3-Xaa5-Xaa3-Xaa4-Arg-Arg-Arg-Asp- Leu-Asn-# Name:Sl14.2 Species: sulcatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:34)GTCTGAAGGTGGTAAACCGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCGTGTCTTGCGAAGTCTGATTTCCCGTCGTCAATCTGGCTGCAGAGTCCCGTTTGAATTGAAATGCATCTGGAAGTTCTGTACAATATACCCATCGAGACCATTTGCTTCTCTGGAAGAAAAAGACGAATGTCAGACAGTCACCATAACTGTAACATGGGATTTTTAATACGTCTCCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKPNDVIRGLVPDDLTPQRVLRSLISRRQSGCRV (SEQ ID NO:35)PFELKCIWKFCTIYPSRPFASLEEKDECQTVTITVTWDF Toxin Sequence:Xaa2-Ser-Gly-Cys-Arg-Val-Xaa3-Phe-Xaa1-Leu-Lys-Cys-Ile- (SEQ ID NO:36)Xaa4-Lys-Phe-Cys-Thr-Ile-Xaa5-Xaa3-Ser-Arg-Xaa3-Phe-Ala-Ser-Leu-Xaa1-Xaa1-Lys-Asp-Xaa1-Cys-Gln-Thr-Val-Thr-Ile-Thr-Val-Thr-Xaa4-Asp-Phe-{circumflex over ( )} Name: Sl14.1 Species:sulcatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCTCTCT (SEQ ID NO:37)GTCTGAAGGTGGTAAACCGAACGACGTCATTCGGGGTTTTGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAAGGATGTTGGGAAGAGAATGGAATGTTACTGGAAGGCATGTAGACCCACGCTATCGAGACGACATGATCTTGGGTAAAAGATGAATGACGTCAGACAACAGCCACAACTATAGTATGACATCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCGTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITASLSEGGKPNDVIRGFVPDDLTPQLILRSLISRRRSDKDV (SEQ ID NO:38)GKRMECYWKACRPTLSRRHDLG Toxin Sequence:Arg-Ser-Asp-Lys-Asp-Val-Gly-Lys-Arg-Met-Xaa1-Cys-Xaa5- (SEQ ID NO:39)Xaa4-Lys-Ala-Cys-Arg-Xaa3-Thr-Leu-Ser-Arg-Arg-His-Asp- Leu-# Name: M14.1Species: magus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGCTGATGATGATGGTGTGCATCACAGCCCCTCT (SEQ ID NO:40)GCCTGAAGGTGGTAAACCGAACAGCGGAATTCGGGGTTTGGTGCCAAACGACTTAACTCCACAGCATACCTTGCGAAGTCTGATTTCCCGTCGTCAAACTGACGTTCTTCTGGATGCTACCCTTTTGACAACACCAGCCCCCGAGCAGAGATTGTTCTGCTTCTGGAAGTCATGTTGGCCAAGGCCCTACCCTTGGAGACGACGTAATCTTAATGGAAAACGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTAATACGACTTCAGCAAATATTTTAACATAACTGTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTCAGAGTTGTACTGATATGAGCTCTGCCCTGTGAAATAAAGCTG ATGTranslation: MQTAYWVMLMMMVCITAPLPEGGKPNSGIRGLVPNDLTPQHTLRSLISRRQTDVLL(SEQ ID NO:41) DATLLTTPAPEQRLFCFWKSCWPRPYPWRRRNLNGKR Toxin Sequence:Xaa2-Thr-Asp-Val-Leu-Leu-Asp-Ala-Thr-Leu-Leu-Thr-Thr- (SEQ ID NO:42)Xaa3-Ala-Xaa3-Xaa1-Gln-Arg-Leu-Phe-Cys-Phe-Xaa4-Lys-Ser-Cys-Xaa4-Xaa3-Arg-Xaa3-Xaa5-Xaa3-Xaa4-Arg-Arg-Arg-Asn- Leu-Asn-# Name:Em14.1 Species: emaciatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGCGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:43)GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATGACTTAACCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATACTCACGGCATTCGTCCGAAGGGAGACGGCATATGTATCTGGAAGGTATGTCCACCAGACCCATGGAGACGACATCGTCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTCAAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGATGTCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMAMMMVWITAPLSEGGKLNDVIRGLVPDDLTPQLVLQSLDSRRHTHGIR (SEQ ID NO:44)PKGDGICIWKVCPPDPWRRHRLKKRNN Toxin Sequence:His-Thr-His-Gly-Ile-Arg-Xaa3-Lys-Gly-Asp-Gly-Ile-Cys- (SEQ ID NO:45)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Asp-Xaa3-Xaa4-Arg-Arg-His-Arg-Leu-Lys-Lys-Arg-Asn-Asn-{circumflex over ( )} Name: Cr14.1Species: circumcisus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGGTGGTGTGGATTACAGCCCCTCT (SEQ ID NO:46)GTCTGAAGGTGGTAAATCGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTCTTCGTTCTGACAGCAGTGGTCAGAAAGGAGCACAAATATGCATCTGGAAGGTATGTCCACTATCCCCATGGAGACGACCACAAGGAAAAAGATGAATGACGTCAGACAACCGCTACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMVVWITAPLSEGGKSNDVIRGLVPHILTPQHILQSLTSRLRSDSSG (SEQ ID NO:47)QKGAQICIWKVCPLSPWRRPQGKR Toxin Sequence:Leu-Arg-Ser-Asp-Ser-Ser-Gly-Gln-Lys-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:48)Ile-Xaa4-Lys-Val-Cys-Xaa3-Leu-Ser-Xaa3-Xaa4-Arg-Arg- Xaa3-Gln-# Name:Bt14.1 Species: betulinus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:49)GTCCGAAGGTGGTAAACTGAACGATGTAATTCGGGCTTTGGCGCCAGACGACGTAACCCCACAGTTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAGCGATGTTCGGGAGGTACCCGTATGTTCCTGGAAGATATGTCCACCATAGCCATAGAGACGACATGATCTTAAGGAAAAAGAGAAATGACGTCAGACAACCGCCACAACTGTAGTACGGCATCGTTAATACGACTTCAGCAAATGTTTTAACATCACTGTGGTTGTGAAGAAATCAGCTGCTTTAAAAGATTGGATTTTTCCTTAAGAGTTGCACTGATGTCAGTTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRALAPDDVTPQFILRSLISRRRSDSDV (SEQ ID NO:50)REVPVCSWKICPP Toxin Sequence:Arg-Ser-Asp-Ser-Asp-Val-Arg-Xaa1-Val-Xaa3-Val-Cys-Ser- (SEQ ID NO:51)Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-{circumflex over ( )} Name: A14.1 Species:aurisiacus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGCGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:52)GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATGACTTAACCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATACTCACGGCATTCGTCCGAAGGGAGACGGCATATGTATCTGGAAGGTATGTCCACCAGACCCATGGAGACGACATCATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTCAAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGATGTCAGCTCTGCCCTATGAAATAAAGCTGATG Translation:MQTAYWVMAMMMVWITAPLSEGGKLNDVIRGLVPDDLTPQLVLQSLDSRRHTHGIR (SEQ ID NO:53)PKGDGICIWKVCPPDPWRRHHLKKRNN Toxin Sequence:His-Thr-His-Gly-Ile-Arg-Xaa3-Lys-Gly-Asp-Gly-Ile-Cys- (SEQ ID NO:54)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Asp-Xaa3-Xaa4-Arg-Arg-His-His-Leu-Lys-Lys-Arg-Asn-Asn-{circumflex over ( )} Name: A14.2Species: aurisiacus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:55)GTCTGAAGGTGGTAAATTGAACGACGTAATTTGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGCCTGACTTCCCGTCTTCATTCTGACAGCAGTGATCAGAAAGGAGGCATGAACGCATGGACAGGAGCAGGAGCACAAATATGCATCTGGAAGGTATGTCCACCACCCCCATGGAGATGAACACAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAGTAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIWGLVPHILTPQHILQSLTSRLHSDSSD (SEQ ID NO:56)QKGGMNAWTGAGAQICIWKVCPPPPWR Toxin Sequence:Leu-His-Ser-Asp-Ser-Ser-Asp-Gln-Lys-Gly-Gly-Met-Asn-Ala- (SEQ ID NO:57)Xaa4-Thr-Gly-Ala-Gly-Ala-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-{circumflex over ( )} Name: A14.3Species: aurisiacus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:58)GTCTGAAGGTGGTAAATTGAACGACGTAATTTGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGCCTGACTTCCCGTCTTCATTCTGACAGCAGTGATCAGAAAGGAGCACAAATATGCATCTGGAAGGTATGTCCACCACCCCCATGGAGATGAACACAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAGGAGTTGTATTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIWGLVPHILTPQHILQSLTSRLHSDSSD (SEQ ID NO:59)QKGAQICIWKVCPPPPWR Toxin Sequence:Leu-His-Ser-Asp-Ser-Ser-Asp-Gln-Lys-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:60)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-{circumflex over ( )}Name: A14.4 Species: aurisiacus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:61)GTTTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGCCTGACTTCCCGTCTTCGTTCTGACAGCAGTGATCAGAAAGGAGGCATGAACGCATCGACAGGAGCAGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACGAACACAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLFEGGKLNDVIRGLVPHILTPQHILQSLTSRLRSDSSD (SEQ ID NO:62)QKGGMNASTGAGAQICIWKVCPPSPWRRTQGKR Toxin Sequence:Leu-Arg-Ser-Asp-Ser-Ser-Asp-Gln-Lys-Gly-Gly-Met-Asn-Ala- (SEQ ID NO:63)Ser-Thr-Gly-Ala-Gly-Ala-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Thr-Gln-# Name: Ac14.1 Species:achatinus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:64)GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTCTTCGTTCTGACAACGGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTGTGTCCACCATCCCCATGGAGACGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQSLTSRLRSDNGG (SEQ ID NO:65)SSGAQICIWKVCPPSPWRRPQGKR Toxin Sequence:Leu-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:66)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg- Xaa3-Gln-# Name:P14.2 Species: purpurascens Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGACGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:67)GTCTGAAGGTGGAAAACTGAACGATGTAATTCGGGGTTTGGTGCCAGACGACTTAGCCCTACAGCTTATCTTGCAAAGTCCGGTTTTCCGTCGTCAATCTGAAGAGGAAAAAATATGCCTCTGGAAGATATGTCCACCACCCCCATGGAGACGATCATAAGGAAAAAAAAATGAATGACGTCAGACAACCACCACAACTGTAATACGACATCGTTAATACGACTTCAGCAAACATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAGAAGCTTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAA GCTGATGTranslation: MQTAYWVMVMTMVWITAPLSEGGKLNDVIRGLVPDDLALQLILQSPVFRRQSEEEK(SEQ ID NO:68) ICLWKICPPPPWRRS Toxin Sequence:Xaa2-Ser-Xaa1-Xaa1-Xaa1-Lys-Ile-Cys-Leu-Xaa4-Lys-Ile- (SEQ ID NO:69)Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Ser-{circumflex over ( )} Name:P14.1 Species: purpurascens Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:70)GTCTGAGGGTAGAAAACCGAACGATGTAATTCGGGGTTTGGTGCCAGATGACTTAGCCCTACAGCTTATCTTGCAAAGTCAGGTTTCCCGTCGTGAATCTAATGGGGTGGAAATATGCATGTGGAAGGTATGTCCACCATCCCCATGGAGACGATCATAAGGAAAAAAAATGAATGACGTCAGACAACCACCACAACTGTAATACGACATCGTTAATACGACTTCAGCAAACATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAAG CTGATGTranslation: MQTAYWVMVMMMVWITAPLSEGRKPNDVIRGLVPDDLALQLILQSQVSRRESNGVE(SEQ ID NO:71) ICMWKVCPPSPWRRS Toxin Sequence:Xaa1-Ser-Asn-Gly-Val-Xaa1-Ile-Cys-Met-Xaa4-Lys-Val-Cys- (SEQ ID NO:72)Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Ser-{circumflex over ( )} Name: Sm14.1Species: stercusmuscarum Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:73)GTCTGAAGGTGGTAAATTGACCGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTATGACTTCCCGTCTTGGTATTGGCAGCAGTGATCAAAATGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATAGAGACGACCATAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKLTDVIRGLVPHILTPQHILQSMTSRLGIGSSD (SEQ ID NO:74)QNAQICIWKVCPPSP Toxin Sequence:Leu-Gly-Ile-Gly-Ser-Ser-Asp-Gln-Asn-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:75)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-{circumflex over ( )} Name: Ba14.1Species: baileyi Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATAATGGTGTGGATTACAGTCCCTCT (SEQ ID NO:76)GTCTGAAGGTGGTAAATTGAACGACATAATTCGGGGTTTGTTGCCAGACAACTTCCCCCCACAGCTTACCTTGCATCGTCTGGTTTCCCGTCGTCATTCTGACAGCATTATTCTGAGGGGCTTATGTATCTGGAAGGTGTGTGAACCTCCGCCACAAAGATGATCTGGTCCAAAGCCAAAAAACGAATGATGTCAGACAACCGCCACAGCTTTAGTACGACATGGTTAATACGACTTCAGCAAATATTTCAACATCACTGTGGTTGTGAAGAAATCAGTTACTTTAAAAGATTGGAATGATGTCAGCTGTGCACTATCAAATAAAGTTGATGTGACAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMIMVWITVPLSEGGKLNDIIRGLLPDNFPPQLTLHRLVSRRHSDSII (SEQ ID NO:77)LRGLCIWKVCEPPPQR Toxin Sequence:His-Ser-Asp-Ser-Ile-Ile-Leu-Arg-Gly-Leu-Cys-Ile-Xaa4- (SEQ ID NO:78)Lys-Val-Cys-Xaa1-Xaa3-Xaa3-Xaa3-Gln-Arg-{circumflex over ( )} Name:Bk14.1 Species: bocki Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:79)GTCTGAAAGTGATAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACAACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAAGGATGATCCGGGAGGACAAGAATGTTACTGGAACGTATGTGCACCAAACCAGGGAGACCACATGATCTTAAGAAAAAAGATGAATGACGACAGACAACCGCCACAACTGTAATACGACATCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCGTGTTTAAGAGCTGTACTGATATCTGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSESDKLNDVIRGLVPDNLTPQLILRSLISRRRSDKDD (SEQ ID NO:80)PGGQECYWNVCAPNQGDHMILRKKMNDDRQPPQL Toxin Sequence:Arg-Ser-Asp-Lys-Asp-Asp-Xaa3-Gly-Gly-Gln-Xaa1-Cys-Xaa5- (SEQ ID NO:81)Xaa4-Asn-Val-Cys-Ala-Xaa3-Asn-Gln-Gly-Asp-His-Met-Ile-Leu-Arg-Lys-Lys-Met-Asn-Asp-Asp-Arg-Gln-Xaa3-Xaa3-Gln- Leu-{circumflexover ( )} Name: Cd14.1 Species: chaldaeus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGGGGATGATG (SEQ ID NO:82)ATGGTGTGGATTACAGCCCCTCTGTCTGGAGGTGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCGAAACTCCGGTTTCCCATCGTCTTTCTGAGGGCAGAAATTCGACGGTACACATATGTACGTGGAAGGTATGTCCACCTCCCCCATGGAGACGACCACATGGACAAAGATGAATGACGTCAGACAACCTCCACAACTGTAGTACGACATCGTTAACACGACGTCAGCTAATCTTTTAACATCACTGTGGCTGTGAAGAACTCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTGCTGATATGAACTCTGCACTACGAAATAAAGCTGATGTGACAAACAAAAAAAAGAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMMGMMMVWITAPLSGGGKLNDVIRGLVPDDLTLQRMFETPVSHRLSEGR (SEQ ID NO:83)NSTVHICTWKVCPPPPWRRPHGQR Toxin Sequence:Leu-Ser-Xaa1-Gly-Arg-Asn-Ser-Thr-Val-His-Ile-Cys-Thr- (SEQ ID NO:84)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-His-Gly-Gln-Arg-{circumflex over ( )} Name: Cd14.2 Species: chaldaeusCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGGGGATGATG (SEQ ID NO:85)ATGGTGTGGATTACAGCCCCTCTGTCTGGAGGTGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCGAAACTCCGGTTTCCCATCGTCTTTCTGAGGGCAGAAATTCGACGGTACACATATGTATGTGGAAGGTATGTCCACCTCCCCCATGGAGACGACCACATGGACAAAGATGAATGACGTCAGACAACCTCCACAACTGTAGTACGACATCGTTAACACGACGTCAGCTAATCTTTTAACATCACTGTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTGCTGATATGAACTCTGCACTACGAAATAAAGCTGATGTGACAAACGGAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMMGMMMVWITAPLSGGGKLNDVIRGLVPDDLTLQRMFETPVSHRLSEGR (SEQ ID NO:86)NSTVHICMWKVCPPPPWRRPHGQR Toxin Sequence:Leu-Ser-Xaa1-Gly-Arg-Asn-Ser-Thr-Val-His-Ile-Cys-Met- (SEQ ID NO:87)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-His-Gly-Gln-Arg-{circumflex over ( )} Name: Ci14.1 Species: cinereusCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGTTG (SEQ ID NO:88)GTGTGGATTACAGCCCCTCTGCCTGAGGGTGGTAAACCGAAGCACGTAATTCGGGGTTTGGTACCAGACGACTTAACCCCACAGCATATCTTGCGAAGTTTGATTTCCCGTCGTTCATCTGGCTGCAGTGTTTCGTTGGGCTTCAAATGCTTCTGGAAGAGCTGTACAGTAATCCCAGTGAGACCATTTGTATCTCTGGAAGAAGAAAATGAATGCCAGAAAGTCCAAATAAGTGCAGTATGGGGTCCTTGATACGACTTCAGCAAGGATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTTGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGTACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMLVWITAPLPEGGKPKHVILGLVPDDLTPQHILRSLISRRSSGCSV (SEQ ID NO:89)SLGFKCFWKSCTVIPVRPFVSLEEENECQKVQISAVWGP Toxin Sequence:Ser-Ser-Gly-Cys-Ser-Val-Ser-Leu-Gly-Phe-Lys-Cys-Phe- (SEQ ID NO:90)Xaa4-Lys-Ser-Cys-Thr-Val-Ile-Xaa3-Val-Arg-Xaa3-Phe-Val-Ser-Leu-Xaa1-Xaa1-Xaa1-Asn-Xaa1-Cys-Gln-Lys-Val-Gln-Ile-Ser-Ala-Val-Xaa4-Gly-Xaa3-{circumflex over ( )} Name: Ci14.2 Species:cinereus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGGTG (SEQ ID NO:91)GTGGTGTGGATTACAGCCCCTCTGCCTGAAGGTGGTAAACCGGAGCACGTAATAATCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTAGTTCTGACGGCAAGGCAAAAAGAAATTGTTTCTGGAAGGCATGTGTACCAGAACAATGGAGACAACGTGATCTTAAGGAAAAAGATGAATGATGTCAGACAACCGCCATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCACTGTGGATCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTCGTTTAAGAGTTGTACTGATGTCAGCTCTGCACTGTGAAATAAAGCTGATGTGACAAACGAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMVVVWITAPLPEGGKPEHVIRGLVPDDLTPQLILRSLISRRSSDGK (SEQ ID NO:92)AKRNCFWKACVPEQWRQRDLKEKDE Toxin Sequence:Ser-Ser-Asp-Gly-Lys-Ala-Lys-Arg-Asn-Cys-Phe-Xaa4-Lys- (SEQ ID NO:93)Ala-Cys-Val-Xaa3-Xaa1-Gln-Xaa4-Arg-Gln-Arg-Asp-Leu-Lys-Xaa1-Lys-Asp-Xaa1-{circumflex over ( )} Name: Ci14.3 Species: cinereusCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:94)GTGGTGTGGATTACAGCCCCTCTGCCTGAAGGTGGTAAACCGAAGCACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTAGTTCTGACGGCAAGGCAAAAAGAAATTGTTTCTGGAAGGCATGTGTACCAGAACAATGGAGACAACGTGATCCTAAGGAAAAAGATGAATGATGTCAGACAACCGCCATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCACTGTGGATCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTCGTTTAAGAGTTGTACTGATGTCAGCTCTGCACTGTGAAATAAAGCTGACGTGACAAGCAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVVWITAPLPEGGKPKHVIRGLVPDDLTPQLILRSLISRRSSDGK (SEQ ID NO:95)AKRNCFWKACVPEQWRQRDPKEKDE Toxin Sequence:Ser-Ser-Asp-Gly-Lys-Ala-Lys-Arg-Asn-Cys-Phe-Xaa4-Lys- (SEQ ID NO:96)Ala-Cys-Val-Xaa3-Xaa1-Gln-Xaa4-Arg-Gln-Arg-Asp-Xaa3-Lys-Xaa1-Lys-Asp-Xaa1-{circumflex over ( )} Name: Ci14.4 Species: cinereusCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATAATGATG (SEQ ID NO:97)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAACCGAAGCACGTAATTCGGGGTTTGGTGCCAGTCGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTAGTTCTGACGGCAAGGCAAAAAAACAATGTGCCTGGAAGACATGTGTACCAACCCAATGGAGACGACGTGATCTTAAGGAAAAAGATGAATGATGTCAGACAACCGCCATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCACTGTGGTTCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTGTGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVIMMVWITAPLSEGGKPKHVIRGLVPVDLTPQLILRSLISRRSSDGKA (SEQ ID NO:98)KKQCAWKTCVPTQWRRRDLKEKDE Toxin Sequence:Ser-Ser-Asp-Gly-Lys-Ala-Lys-Lys-Gln-Cys-Ala-Xaa4-Lys- (SEQ ID NO:99)Thr-Cys-Val-Xaa3-Thr-Gln-Xaa4-Arg-Arg-Arg-Asp-Leu-Lys-Xaa1-Lys-Asp-Xaa1-{circumflex over ( )} Name: Cr14.2 Species:circumcisus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:100)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAGGTCTGACTTCCCGTCTTCGTTCTGACAGCAGTGGTCAGAAAGGAGCACAAATATGCATCTGGAAGGTATGTCCACTATCCCCATGGAGACGACCACAAGGAAAAGATGAATGACGTCAGACAACCGCTACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGCTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQGLTSRLRSDSSG (SEQ ID NO:101)QKGAQICIWKVCPLSPWRRPQGKDE Toxin Sequence:Leu-Arg-Ser-Asp-Ser-Ser-Gly-Gln-Lys-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:102)Ile-Xaa4-Lys-Val-Cys-Xaa3-Leu-Ser-Xaa3-Xaa4-Arg-Arg-Xaa3-Gln-Gly-Lys-Asp-Xaa1-{circumflex over ( )} Name: Cn14.4 Species:consors Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:103)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACTTCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTAATGGTTCTGGCAGCAGTAATCAGAAAGAAGCACAACTATGCATCTGGAAGGTATGTCCACCAACCCCATGGAGATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGTTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHFLTPQHILQSLTSRNGSGSSN (SEQ ID NO:104)QKEAQLCIWKVCPPTPWR Toxin Sequence:Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:105)Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Arg-{circumflex over( )} Name: Cn14.5 Species: consors Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:106)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAACTGAACGGCGTAATTCGGGGTTTGGTGTCACACATCTTAATCCCACAGCATACCTTGCGAAGTCTGACTTCCCGTGATCGTTCTGACAACGGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAAATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCACCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTCGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNGVIRGLVSHILIPQHTLRSLTSRDRSDNGG (SEQ ID NO:107)SSGAQICIWKVCPPSPWK Toxin Sequence:Asp-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:108)Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Lys-{circumflex over ( )}Name: Ct14.1 Species: coronatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGATGATGATGATGATGGTGTGGATTACAGCCCC (SEQ ID NO:109)TCTGTCTGAAGGTGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCAAAGCTCTGGTTTCCCATCGTCTTTCTGACGGCAGAGATTGGACGGGATACATATGTATCTGGAAGGCATGTCCACGTCCCCCATGGATCCCACCAAAGGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTAACACAACTTCAGCTAATATTTTAACATCACTGTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGAATTTTTCGTTTAAGAGTTGTGCTGATACGAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGT TGTTACTCGAGTranslation: MQTAYWVMMMMMMVWITAPLSEGGKLNDVIRGLVPDDLTLQRMFKALVSHRLSDGR(SEQ ID NO:110) DWTGYICIWKACPRPPWIPPKGKR Toxin Sequence:Leu-Ser-Asp-Gly-Arg-Asp-Xaa4-Thr-Gly-Xaa5-Ile-Cys-Ile- (SEQ ID NO:111)Xaa4-Lys-Ala-Cys-Xaa3-Arg-Xaa3-Xaa3-Xaa4-Ile-Xaa3-Xaa3- Lys-# Name:Eb14.1 Species: ebraeus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGATGATG (SEQ ID NO:112)ATGGTGTGGATTACAGCCCCTCTGTCTGAAGGCGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCAAAAGTCTGTTTTCCCATCGTCTTTCTGGCGGCACATATTCGAGGGTAGACACATGCATCTGGAAGGTATGTCCACAATCTCCATAGGGACGATCATATGGAAAAAGATGAGTGACATCAGACAACTGCCACAACTGTAGTACGACATCGTTAACACGACTTCAGCTAATATTTTAACATCACTGTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTGCTGATATGAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMMMMMMVWITAPLSEGGKLNDVIRGLVPDDLTLQRMFKSLFSHRLSGGT (SEQ ID NO:113)YSRVDTCIWKVCPQSP Toxin Sequence:Leu-Ser-Gly-Gly-Thr-Xaa5-Ser-Arg-Val-Asp-Thr-Cys-Ile- (SEQ ID NO:114)Xaa4-Lys-Val-Cys-Xaa3-Gln-Ser-Xaa3-{circumflex over ( )} Name: G14.2Species: geographus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGCTGATGATGATG (SEQ ID NO:115)GTGTGCATCACAGCCCCTCTGCCTGAAGGTGGTAAACCGAACAGCGGAATTCGGGGTTTGGTGCCAAACGACTTAACTCCACAGCATACCTTGCGAAGTCTGATTTCCCGTCGTCAAACTGACGTTCTTCTGGAGGCTACCCTTTTGACAACACCAGCCCCCGAGCAGAGATTGTTCTGCTTCTGGAAGTCATGTACGTGGAGGCCCTACCCTTGGAGACGACGTGATCTTAATGGAAAACGATGAATGACGCCAGACAACCGCCACAACTGTAGTACGACATCGTTAATACGACTTCAGCAAACATTTTAACATAACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTCAGAGTTGTACTGATATGAGCTCTGCACCATGAAATAAAGCTGAAGTGACGAACAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMLMMMVCITAPLPEGGKPNSGIRGLVPNDLTPQHTLRSLISRRQTDVLL (SEQ ID NO:116)EATLLTTPAPEQRLFCFWKSCTWRPYPWRRRDLNGKR Toxin Sequence:Xaa2-Thr-Asp-Val-Leu-Leu-Xaa1-Ala-Thr-Leu-Leu-Thr-Thr- (SEQ ID NO:117)Xaa3-Ala-Xaa3-Xaa1-Gln-Arg-Leu-Phe-Cys-Phe-Xaa4-Lys-Ser-Cys-Thr-Xaa4-Arg-Xaa3-Xaa5-Xaa3-Xaa4-Arg-Arg-Arg-Asp- Leu-Asn-# Name:Gd14.1 Species: gladiator Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGGTTACAGTCCCTCG (SEQ ID NO:118)ATCTGAAGGTGGCACGTGGAACTACTTAATTCGGGGTTTGGTGCCAGACGACCTAACCCCACAGCTTACCTTGCATCGTCTGGTTACCCGTCGTCATCCTGCCAACGTTAGACAGCAGGGGAAAATATGTGTATGGAAGGTGTGTCCACCATGGCCAGTAAGATCACCTGGTCCACAGCCAAAAAACAAATGACGTCAGACAACCGCCACAACTTTAGTACGACATCGTTGATACAACTTCAGCAAGTATTTTAACATCACTGTGGCTCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTTAGAGTTTTACTGATATCAGCTCTGCACTATGAAATAAAGATGTGACGAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTG TTACTCGAGTranslation: MQTAYWVMVMMMVWVTVPRSEGGTWNYLIRGLVPDDLTPQLTLHRLVTRRHPANVR(SEQ ID NO:119) QQGKICVWKVCPPWPVRSPGPQPKNK Toxin Sequence:His-Xaa3-Ala-Asn-Val-Arg-Gln-Gln-Gly-Lys-Ile-Cys-Val- (SEQ ID NO:120)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa4-Xaa3-Val-Arg-Ser-Xaa3-Gly-Xaa3-Gln-Xaa3-Lys-Asn-Lys-{circumflex over ( )} Name: Gd14.2Species: gladiator Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGGTTACAGTCCCTCG (SEQ ID NO:121)ATCTGAAGGTGGCACGTGGAACTACTTAATTCGGGGTTTGGTGCCAGACGACCTAACCCCACAGCTTACCTTGCATCGTCTGGTTACCCGTCGTCATCCTGCCAACGTTAGACAGCAGGGGAAAATATGTGTATGGAAGGTGTGTCCACCATCGCCAGTAAGATCACCTGGTCCACTGCCAAAAAACAAATGACGTCAGACAACCGCCACAACTTTAGTACGACATCGTTGATACAACTTCAGCAAGTATTTTAACATCACTGTGGCTCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTTAGAGTTTTACTGATATCAGCTCTGCACTATGAAATAAAGATGTGACGGACAAAAAAAAAAAAAAAAAAGTACTCTGCGT TGTTACTCGAGTranslation: MQTAYWVMVMMMVWVTVPRSEGGTWNYLIRGLVPDDLTPQLTLHRLVTRRHPANVR(SEQ ID NO:122) QQGKICVWKVCPPSPVRSPGPLPKNK Toxin Sequence:His-Xaa3-Ala-Asn-Val-Arg-Gln-Gln-Gly-Lys-Ile-Cys-Val- (SEQ ID NO:123)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Val-Arg-Ser-Xaa3-Gly-Xaa3-Leu-Xaa3-Lys-Asn-Lys-{circumflex over ( )} Name: Ly14.1Species: litoglyphus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:124)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGATAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATAACTTAGCCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATCCTCACGGCATTCGTCAGGATGGAGCCCAAATATGTATCTGGAAGATATGTCCACCATCCCCATGGAGACGACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACATCTTGAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGATGTCATCTCTGCACTATGAAATAAAGCTGATGTGAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLQSLDSRRHPHGIR (SEQ ID NO:125)QDGAQICIWKICPPSPWRRLGS Toxin Sequence:His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:126)Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Leu-Gly-Ser-{circumflex over ( )} Name: Ly14.2 Species: litoglyphusCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:127)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGATAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATAACTTAGCCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATCCTCACGGCATTCGTCAGGATGGAGCCCAAATATGTATCTGGAAGATATGTCCACCATCCCCATGGAAACGACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTACGACATCGTTAATACAACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAGGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGATGTCATCTCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAA TTCTranslation: MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLQSLDSRRHPHGIR(SEQ ID NO:128) QDGAQICIWKICPPSPWKRLGS Toxin Sequence:His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:129)Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Lys-Arg-Leu-Gly-Ser-{circumflex over ( )} Name: Lt14.1 Species: litteratusCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:130)GTGGGGATTACAGCCCCTCTGTCTGAAGGTCGTAAATTGAACGACGCAATTCGGGGTTTGGTGCCAGATGACTTAACCCCACAGCTTTTGCGAAGTCCGGTTTCGACTCCTTATCCTGAGTTTCATCTTGATGAACCTTATCTGAAGATACCCGTATGTATCTGGAAGATATGTCCACCAAACCTATTGAGACGACGTGATCTTAAGAAAAGAAACAAAGTACGTCAGACAACCGCCACAACTTGAGTACGACATCGTTCATACAACTTGAGCAAATATTTCAGCATCACTATGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATCTTTCCTTGTTTAAGAGTTGTATTGATGTCAGCTCTGCACTCTGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAA TTCTranslation: MQTAYWVMVMMMVGITAPLSEGRKLNDAIRGLVPDDLTPQLLRSPVSTPYPEFHLD(SEQ ID NO:131) EPYLKIPVCIWKICPPNLLRRRDLKKRNKVRQTTATT Toxin Sequence:Ser-Xaa3-Val-Ser-Thr-Xaa3-Xaa5-Xaa3-Xaa1-Phe-His-Leu- (SEQ ID NO:132)Asp-Xaa1-Xaa3-Xaa5-Leu-Lys-Ile-Xaa3-Val-Cys-Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Asn-Leu-Leu-Arg-Arg-Arg-Asp-Leu-Lys-Lys-Arg-Asn-Lys-Val-Arg-Gln-Thr-Thr-Ala-Thr-Thr-{circumflex over( )} Name: Lt14.2 Species: litteratus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:133)GTGGGGATTACAGCCCCTCTGTCTGAAGGTCGTAAATTGAACGACGCAATTCGGGGTTTGGTGCCAAATGACTTAACCCCACAGCTTTTGCAAAGTCTGGTTTCCCGTCGTCATCGTGTGTTTCATCTTGACAACACTTATCTCAAGATACCCATATGTGCCTGGAAGGTATGTCCACCAACCCCATGGAGACGACGTGATCTTAAGAAAAGAAACAAATGACGTCAGACAACCGCCACAACTTGAGTACGACATTGTTAATGCGACTTGAGCAAATTTTTCAGCATCACTATGGTTGTAAAGAAATCAGCTGCTTTAAACGATTGGATCTTTCCTTATTTAAGAGTTGTATTGATGTCAGCTCTGCACTCTGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGA ATTCTranslation: MQTAYWVMVMMMVGITAPLSEGRKLNDAIRGLVPNDLTPQLLQSLVSRRHRVFHLD(SEQ ID NO:134) NTYLKIPICAWKVCPPTPWRRRDLKKRNK Toxin Sequence:His-Arg-Val-Phe-His-Leu-Asp-Asn-Thr-Xaa5-Leu-Lys-Ile- (SEQ ID NO:135)Xaa3-Ile-Cys-Ala-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Arg-Arg-Arg-Asp-Leu-Lys-Lys-Arg-Asn-Lys-{circumflex over ( )} Name:Ls14.1 Species: loroisii Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:136)GTGTGGATTAAAGGCCCTGTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCAAAGTCTGATGTCCCGTCGTCGTTCTGACAGCGATGTTCGGGAGGTGTACATATTATGCATCTGGAAGATATGTCCACCATTGCCATGAAGACGACATGATCTTAAGGAAAAGGATAAACGACGTCAGACAACCGCTACAACTGTAGTACGACATCGTTAATACGACTTCAGCAAATATTTGAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAACGATTGGATTTTTCCTTAAGAGTTGCACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACTACCAAAAAAAAAAAAAAAAAAAAGTACTNTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWIKGPVSEGGKLNDVIRGLVPDDLTPQLILQSLMSRRRSDSDV (SEQ ID NO:137)REVYILCIWKICPPLP Toxin Sequence:Arg-Ser-Asp-Ser-Asp-Val-Arg-Xaa1-Val-Xaa5-Ile-Leu-Cys- (SEQ ID NO:138)Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Leu-Xaa3-{circumflex over ( )} Name:M14.2 Species: magus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:139)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACTCCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTAATGGTTCTGGCAGCAGCAATCAGAAAGAAGCACAACTATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTGGGACATCGTTGATACGACTTCAACAAATATTTTAACATCACTGTGGTTGTAAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHSLTPQHILQSLTSRNGSGSSN (SEQ ID NO:140)QKEAQLCIWKVCPPSPWR Toxin Sequence:Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:141)Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-{circumflex over( )} Name: Mi14.3 Species: miles Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGGTGGTG (SEQ ID NO:142)ATGATGGTGGGGGTTACTGTCGCTGGCTCCCTGCCTGTGTTTGATGACGACAACGACTCTGACCCCGCTGTCAAGCGCGCTATCACGTGGTCCCGCATCCTGGGCGTGTCTCCAGCCTTCCTGGCACAGCAGCGAGCGCTGGTTCCCTTCGCCAACCGATTCATCAGTGAGCAGAAACGTTTCCGACCCGCCATGCAGAGCCGATCAGGAGGAATGTCGCTGTGCCTATGGAAAGTGTGTCCTGCAGCCCCCTGGCTGGTCGCCAAACGTAAACAGGAAACCAGCGACTACTGACGTCATACCTCTAAAGACCCACTCATGACGTCAACGCTGAACTGACGTCACCGACAGCTCCAACGTCACAGCAGGAGCGAGAGAGAGGCTGGAGCATTTCTCTTTCTTTTGGTTTTTCGAGTTGAAGTGTGATCAGCTGGGCTGGTGAAAAAATTGTTGAGTAAAGTTGAATGAAAATCAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGGTACTCGAGGCTTAAAGGCGNAATTC Translation:MQTAYWVMMMVVMMVGVTVAGSLPVFDDDNPSDPAVKRAITWSRILGVSPAFLAQQ (SEQ ID NO:143)RALVPFANRFISEQKRFRPAMQSRSGGMSLCLWKVCPAAPWLVAKRKQETSDY Toxin Sequence:Phe-Arg-Xaa3-Ala-Met-Gln-Ser-Arg-Ser-Gly-Gly-Met-Ser- (SEQ ID NO:144)Leu-Cys-Leu-Xaa4-Lys-Val-Cys-Xaa3-Ala-Ala-Xaa3-Xaa4-Leu-Val-Ala-Lys-Arg-Lys-Gln-Xaa1-Thr-Ser-Asp-Xaa5-{circumflex over ( )}Name: Mi14.4 Species: miles Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:145)GTGGTGGGTTCACCGTCGGGAGTCACGTCCATCGGTCTCACAGTCCTACGTCGCGCAACCATGGTGATGACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGTGTATGCGCCGGGCCAGGCACGTGTGCGTTCTACTTTTGTTCTTGACCTCATTGCAGATAGGGGTTGGTGCAGACGACATGAAACTACAGCGCCAAAGACGTCAAGGTTTCTGTTGCGTCGTTATCCCGATTCTTTGGTTCTGTTGTGGGGGTTACCGCACAAATGGCACTGCACTGGCCGATTGAAAGAACTGCAATAAACGGAATGGCAAGAAGGAATAAAAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVVGSPSGVTSIGLTVLRRATMVMTPFMTRRFINICLPVFLWRTT (SEQ ID NO:146)TTIVLWIFLQCMRRARHVCVLLLFLTSLQIGVGADDMKLQRQRRQGFCCVVIPILW FCCGGYRTNGTALADToxin Sequence: Xaa2-Gly-Phe-Cys-Cys-Val-Val-Ile-Xaa3-Ile-Leu-Xaa4-Phe-(SEQ ID NO:147) Cys-Cys-Gly-Gly-Xaa5-Arg-Thr-Asn-Gly-Thr-Ala-Leu-Ala-Asp-{circumflex over ( )} Name: Mu14.1 Species: muriculatus Cloned: YesDNA Sequence: ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTTT(SEQ ID NO:148) GTCTGAAGGTGGTAAACTGAACGATGTAATTCGGGGTTTCGCGCTAGATGACTTAGCCCAAAGCCGTATTATGCAAAGTCTGGTTTTCAGTCATCAGCCTCTTCCAACGGCATCCATATGTATCTGGAAGATATGTCCACCAGACCCATGGAGACGACATGATCTTCAGAAAAGTAACAAATGACGTCAGACAACCGCCACAACTTGAATACAACATCATTAATACGACTTCAGCAAATATTTTAACATCACTGTGATTGTTCGGAAGTCAGTTGCTTTAAAGGATTGGATTTGTCCCTGTTGTATTGATGTCAACTCTGCACTATGAAATAAAGCTGATGTGACAAACAAGAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCG AG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGFALDDLAQSRIMQSLVFSHQPLPTA (SEQ ID NO:149)SICIWKICPPDPWRRHDLQKSNK Toxin Sequence:Ile-Met-Gln-Ser-Leu-Val-Phe-Ser-His-Gln-Xaa3-Leu-Xaa3- (SEQ ID NO:150)Thr-Ala-Ser-Ile-Cys-Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Asp-Xaa3-Xaa4-Arg-Arg-His-Asp-Leu-Gln-Lys-Ser-Asn-Lys-{circumflex over ( )}Name: Ms14.1 Species: musicus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGATGATGACGATGATGGTGTGGATGACAGCCCC (SEQ ID NO:151)TCTGTCTGAAGGTCGTCCACTGAGCGACGAAGTTCGGGGTATGGTGCCAGGCGACTTGGTCCTACAGTATCTGTTCCCAAGTCTGGCTTTCAGTCCTCCGGACATATGTACGTGGAAGGTATGTCCACCACCCCCATGGAGACGACCAAAAAAAATAACAGACGTCAGACAGCCGCCACAACTGTAGTACGACATCGTTGATACGGCTTCAGCAAATATTTTCAACATCACTGCGGTTGTGAAGAAATCAGTTGCTTTAAAATGTTGGATTTTTCCTTGTTTAAAAGAGCTGTACTGATGTCAGCCCTGCATTACGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMMMTMMVWMTAPLSEGRPLSDEVRGMVPGDLVLQYLFPSLAFSPPDICT (SEQ ID NO:152)WKVCPPPPWRRPKXITDVRQPPQL Toxin Sequence:Gly-Met-Val-Xaa3-Gly-Asp-Leu-Val-Leu-Gln-Xaa5-Leu-Phe- (SEQ ID NO:153)Xaa3-Ser-Leu-Ala-Phe-Ser-Xaa3-Xaa3-Asp-Ile-Cys-Thr-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-Lys-Lys-Ile-Thr-Asp-Val-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}Name: Ms14.2 Species: musicus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGATGATGATGATGATGGTGTGGATGACAGCCCC (SEQ ID NO:154)TCTGTCTGAAGGTCGTAAACTGATCGACAAAGTTCGGGGTATGGGGCCAGGCGACTTATCCCTACAGAAAATGTTCCCAAGTCTGGCTTTAGGTCCTGGGGGAGACGTAATATGTAGGTGGAAGGTATGTCCACCAACCCCATGGAAACGACTAATAAAATAACTGACGTCAGACAGCCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTCAACATCACTGCGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAAGAGTTGTACTGATATCAGCTCTGCATTACGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMMMMMMVWMTAPLSEGRKLIDKVRGMGPGDLSLQKMFPSLALGPGGD (SEQ ID NO:155)VICRWKVCPPTPWKRLIK Toxin Sequence:Gly-Met-Gly-Xaa3-Gly-Asp-Leu-Ser-Leu-Gln-Lys-Met-Phe- (SEQ ID NO:156)Xaa3-Ser-Leu-Ala-Leu-Gly-Xaa3-Gly-Gly-Asp-Val-Ile-Cys-Arg-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Lys-Arg-Leu-Ile-Lys-{circumflex over ( )} Name: Ms14.3 Species: musicus Cloned:Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGATGATGATGACGATGATGGTGTGGATGACAGC (SEQ ID NO:157)CCCTCTGTCTGAAGGTCGTCCACTGAGCGACAAAGTTCGGGGTATGGTGCCAGGCGACTTAGCCCTGCAGTATCTGTTCCCAAGTCTGGCTTTCAATCCCCCGGACATATGTACGTGGAAGGTATGTCCACCACCCCCATGGAGACGACCAAAAAAAATAACTGACGTCGGACAGCCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTCAACATCACTGCGGTTGTGAAGAAATCAGTTGTTTTAAAAGGTTGGATTTTTCCTTGTTTAAAAGAGCTGTACTGATGTCAGCTCTGCATTACGAAATAAAGCTGATGTGACAAACGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGA G Translation:MQTAYWVMMMMTMMVWMTAPLSEGRPLSDKVRGMVPGDLALQYLFPSLAFNPPDIC (SEQ ID NO:158)TWKVCPPPPWRRPKKITDVGQPPQL Toxin Sequence:Gly-Met-Val-Xaa3-Gly-Asp-Leu-Ala-Leu-Gln-Xaa5-Leu-Phe- (SEQ ID NO:159)Xaa3-Ser-Leu-Ala-Phe-Asn-Xaa3-Xaa3-Asp-Ile-Cys-Thr-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-Lys-Lys-Ile-Thr-Asp-Val-Gly-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}Name: Ms14.4 Species: musicus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGATGATGACGATGATGGTGTGGATGACAGCCCC (SEQ ID NO:160)TCTGTCTGAAGGTCGTCCACTGAGCGACAAAGTTCGGGGTATGGTGCCAGGCGACTTAGTCCTGCAGTATCTGTTCCCAAGTCTGGCTTTCAATCCTCCGGACATATGTACGTGGAAGGTATGTCCACCACCCCCATGGAGACGACCAAAAAAAATAACTGACGTCAGACAGCCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTCAACATCACTGCGGTTGTGAAGAAATCAGTTGTTTTAAAAGGTTGGATTTTTCCTTGTTTAAAAGAGCTGTACTGATGTCAGCTCTGCATTACGAAATAAAGCTGATGTGACAAGCAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMMMTMMVWMTAPLSEGRPLSDKVRGMVPGDLVLQYLFPSLAFNPPDICT (SEQ ID NO:161)WKVCPPPPWRRPKKITDVRQPPQL Toxin Sequence:Gly-Met-Val-Xaa3-Gly-Asp-Leu-Val-Leu-Gln-Xaa5-Leu-Phe- (SEQ ID NO:162)Xaa3-Ser-Leu-Ala-Phe-Asn-Xaa3-Xaa3-Asp-Ile-Cys-Thr-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-Lys-Lys-Ile-Thr-Asp-Val-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}Name: Mt14.2 Species: mustelinus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGCGTGGTATACAACCCCTGT (SEQ ID NO:163)GTCTGAATGTGGGAAATTGAACAACGTAATTCGGGGTTTTGTGCCAAAGGACTGGACCCCAATGCTTCCCTGGCGTCGTCTAGTTTCCCATACCAGCAGCAAGTATCCAGGTGTGACTTTTTGTCCATGGAAGGTGTGTCCGCCAGCGCCATGGAGAATACTTGGGGTCTAACGCAAAAAAATACATGACGTCAGACAACCGCCACCGCTTTAGTACGACATCGTTCATACGTCTCCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAGTCAGTAGCTTTAAAAGATTGGATTTTTTCCTTGTTTAAGAGTTGTACTGACATGAGTTCTGCACTATGAAATAAAGTTGATGTGACGAACGAAAAAAAAAAAAAAAAAAAAGTACTCTG CGTTGTTACTCGAGTranslation: MQTAYWVMVMMMAWYTTPVSECGKLNNVIRGFVPKDWTPMLPWRRLVSHTSSKYP(SEQ ID NO:164) GVTFCPWKVCPPAPWRILGV Toxin Sequence:Leu-Val-Ser-His-Thr-Ser-Ser-Lys-Xaa5-Xaa3-Gly-Val-Thr- (SEQ ID NO:165)Phe-Cys-Xaa3-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ala-Xaa3-Xaa4-Arg-Ile-Leu-Gly-Val-{circumflex over ( )} Name: Nb14.1 Species: nobilisCloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGGTGGTG (SEQ ID NO:166)GTGATGATGGTGGGGGTTACTGTCGCTGGCTCACTGTCTGTGTTTGATGATGACAACGACTCTGACCCAGCTGTCAAGCGCGCCATCACGTGGTCTCGATTCCTGGGCGCGTCTCCAGCCTTCCTGGCACAGCAGCGAGCGCTGGCTCCCTTCGCCAACCGACCCATCAATGAGCAGAAACGTTTCCGACCTGCCGTGAAGAGCCGATCACGACGAGCGCCGCCGTGCGTGTGGAAGGTGTGTCCCGCTCCCCCCTGGCTGGTCACCAAACGTAAACAGGAAACCAGCGACTACTGACGTCATACCTCAATAGACCGACTCATGACTTCAACGCTGAATTGACGTCACCGAGAGCTCCAACGTCACAGCAGGAGCGAGAGAGAGAGAGAGAGAGAGAGAAAGAGAGAGAGAAAGGCTGGAGTATTTCTCTTTCTTTTGGTTTTTCGTGTTGAAGTGTGATCAGCTGGGCTGGTTCAAAATTGTTGAATAAAGTTGAATGAAAATCAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAA TTCTranslation: MQTAYWVMMMVVVMMVGVTVAGSLSVFDDDNDSDPAVKRAITWSRFLGASPAFLA(SEQ ID NO:167) QQRALAPFANRPINEQKRFRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDYToxin Sequence: Phe-Arg-Xaa3-Ala-Val-Lys-Ser-Arg-Ser-Arg-Arg-Ala-Xaa3-(SEQ ID NO:168) Xaa3-Cys-Val-Xaa4-Lys-Val-Cys-Xaa3-Ala-Xaa3-Xaa3-Xaa4-Leu-Val-Thr-Lys-Arg-Lys-Gln-Xaa1-Thr-Ser-Asp-Xaa5-{circumflex over ( )}Name: Nb14.2 Species: nobilis Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:169)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACTTCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTAATGGTTCTGGCAGCAGTAATCAGAAAGAAGCGCAACTATGCATCTGGAAGGTATGTCCACCAACCCCATGGAGATGATCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGTTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHFLTPQHILQSLTSRNGSGSSN (SEQ ID NO:170)QKEAQLCIWKVCPPTPWR Toxin Sequence:Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:171)Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Arg-{circumflex over( )} Name: Nb14.3 Species: nobilis Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGGTGGTG (SEQ ID NO:172)GTGATGATGGTGGGGGTTACTGTCGCTGGCTCACTGTCTGTGTTTGATGACGACAATGACTCTGACCCAGCTGTCAAGCGCGCCATCACGTGGTCTCGATTCCTGGGCGCGTCTCCAGCCTTCCTGGCACAGCAGCGAGCGCTGGCTCCCTTCGCCAACCGACCCATCAATGAGCAGAAACGTTTCCGACCTGCCGTGAAGAGCCGATCACGACGAGCGCCGCCGTGCGTATGGAAGGTGTGTCCCGCTCCCCCCTGGCTGGTCACCAAACGTAAACAGGAAACCAGCGACTACTGACGTCATACCTCAATAGACCGACTCATGACTTCAACGCTGAATTGACCTCACCGAGAGCTCCAACGTCACAGCAGGAGCGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAAAGGCTGGAGTATTTCTCTTTCTTTCGGTTTTTCGTGTTGAAGTGTGATCAGCTGGGCTGGTTCAAAATTGTTGAATAAAGTTGAATAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMMMVVVMMVGVTVAGSLSVFDDDNDSDPAVKRITWSRFLGASPAFLA (SEQ ID NO:173)QQRALAPFANRPINEQKRFRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY Toxin Sequence:Phe-Arg-Xaa3-Ala-Val-Lys-Ser-Arg-Ser-Arg-Arg-Ala-Xaa3- (SEQ ID NO:174)Xaa3-Cys-Val-Xaa4-Lys-Val-Cys-Xaa3-Ala-Xaa3-Xaa3-Xaa4-Leu-Val-Thr-Lys-Arg-Lys-Gln-Xaa1-Thr-Ser-Asp-Xaa5-{circumflex over ( )}Name: Pr14.1 Species: parius Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:175)GTGGTGTGGATTACAGCCCCTTTGTCTGAAGGTGGTAAACCGAAGCACGCAATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTAGTTCTTTCGGCAAGGATGCGAAACCCCCCTTTAGTTGTTCAGGCCTCCGAGGGGGTTGCGTCCTACCTCCCAATCTCAGGCCAAAGTTCAACAAAGGTGGATAACAAACCCAAGCGTTCCTAGTTATACGAATGCCAGCAAATAAAAGCAGTTTGATTGTGAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVVWITAPLSEGGKPKHAIRGLVPDDLTPQLILRSLISRRSSFGK (SEQ ID NO:176)DAKPPFSCSGLRGGCVLPPNLRPKFNKGG Toxin Sequence:Xaa3-Xaa3-Phe-Ser-Cys-Ser-Gly-Leu-Arg-Gly-Gly-Cys-Val- (SEQ ID NO:177)Leu-Xaa3-Xaa3-Asn-Leu-Arg-Xaa3-Lys-Phe-Asn-Lys-Gly-# Name: Pr14.2Species: parius Cloned: Yes DNA Sequence:GAATTCGCCCTTGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGT (SEQ ID NO:178)GATGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAACCGAAGCTCATAATTCGGGGTTTGGTGCCAAACGACTTAACCCCACAGCGTATCTTGCGAAGTCTGATTTCCGGGCGTACTTATGGCATCTATGATGCGAAACCCCCCTTTAGTTGTGCAGGCCTCCGAGGGGGTTGCGTCCTACCTCCCAATCTCAGGCCAAAGTTCAAGGAAGGTCGATAAAAAACCCAAGCGTTCCTAGTTATACGAATGCCAGCAAATAAAAGCAGTTTGATTGCGAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVMWITAPLSEGGKPKLIIRGLVPNDLTPQRILRSLISGRTYGIY (SEQ ID NO:179)DAKPPFSCAGLRGGCVLPPNLRPKFKEGR Toxin Sequence:Xaa3-Xaa3-Phe-Ser-Cys-Ala-Gly-Leu-Arg-Gly-Gly-Cys-Val- (SEQ ID NO:180)Leu-Xaa3-Xaa3-Asn-Leu-Arg-Xaa3-Lys-Phe-Lys-Xaa1-# Name: Pl14.1 Species:planorbis Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGATGATG (SEQ ID NO:181)GTGTGGATTACAGGCCATCTGTCTGAAGGTGGCAAATTGAAGGATGCAATTAGGGGTTTGGTGCCAGACGACTTGACCTCAATGTTTGCGTTGCATCTTCCGGTTTCCCATTCTCGGTCTAGCAGCAATGGTCTGAAGAGAGCTGACCTATGTATCCACAAGATTTGTCCACCACGGTATCACCAAAGCCAACAATAAAAGACGTCAGACAACCACCACAACTTTAGTATGACATCGTTAATAGGACTTCAGCAAGTATTTTAACATCACTGTGGTTGTGATGAAATCAGTCGCCTTAAAAGATTGGCTTTTTCCTTGTTTAAGAGTTGTACTTGTATCAGCTTTGCACTTCGAAATAAAGTTGATGTGATGAACCAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMMMMMVWITGHLSEGGKLKDAIRGLVPDDLTSMFALHLPVSHSRSSSNG (SEQ ID NO:182)LKRADLCIHKICPPRYHQSQQ Toxin Sequence:Ser-Ser-Ser-Asn-Gly-Leu-Lys-Arg-Ala-Asp-Leu-Cys-Ile-His- (SEQ ID NO:183)Lys-Ile-Cys-Xaa3-Xaa3-Arg-Xaa5-His-Gln-Ser-Gln-Gln-{circumflex over ( )}Name: Pu14.1 Species: pulicarius Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGATGGTGTGGGTTACAGCGCC (SEQ ID NO:184)TGTGTCTGAAGGTGGTAAATTGAGCGACGTAATTCGGGGTTTGGTGCCAGACGACATAACCCCACAGATTATTTTGCAAAGTCTGAATGCCAGTCGTCATGCTTACAGACGTGTTCGTCTGAGAGGACAGATATGTATCTGGAAGGTATGTCCACCACTACTACAATGGATACATCCATTAGTAAAAAGATGAATGACATCAGACAACCGCCACAACTGTAGTACGACATCGTTAACACGACTTCAGCAAATATTCTAACATCACAGTGGGTTGTGAAGANATCGGGTTGGCTTTAAAAAAAANAATGGGGGNTTTTCCCCNTGGGTTTAAAAAAANNTNGGNNCCGGGNAANNNCCCNNNNTNNNCCCCCCCCNNTNGGGAGAAAAAAAAAANNCCNNTNNNGGGGGGNNNNCNAAAAAAAAAAAAAAAAAAAAAAAAAAAAAANCCCCNGGGGGGNTGNTTTNNCCCCCCNCCCCNGGGGGGGGGGGNGNTTTNNCCCCCCCCCCGNGGGGGGGGGGGNTTTTNNTTTNNGGGGGNGCCCCCCCCCCCCCCNNNCNNNNNAANAANNNNNGGGGGGGGGGAANAAAAANANNNNNNNNNNNNNNNNNNTTTTNTCNNTCNNCCGNGNNGNNAAAAAAAAAANTTNATTTNTNNANNNCNNCNNNCCNNCNNCNNACCCNNCCCCNNCCNCNNCANNCNNAGANNANGAGGGGGGGGNGNNNNGGNGNANNNNNANNNNNNNGAANNNGAGGNGNGNNNCNCGNCNNCGCNCNNGNC Translation:MQTAYWVMVMMMMVWVTAPVSEGGKLSDVIRGLVPDDITPQIILQSLNASRHAYRR (SEQ ID NO:185)VRLRGQICIWKVCPPLLQWIHPLVKR Toxin Sequence:Val-Arg-Leu-Arg-Gly-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-Cys- (SEQ ID NO:186)Xaa3-Xaa3-Leu-Leu-Gln-Xaa4-Ile-His-Xaa3-Leu-Val-Lys- Arg-{circumflexover ( )} Name: Pu14.2 Species: pulicarius Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGATGGTGTGGGTTACAGCGCC (SEQ ID NO:187)TGTGTCTGAAGGTGGTAAATTGAGCGACGTAATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGATTATCTTGCAAAGTCTGAATGCCAGTCGTCATGCTTACAGACGTGTTCGTCCGAGAGGACAGATATGTATCTGGAAGGTATGTCCACCACTACTACAATGGATACATCCATTAGTAAAAAGATGAATGACATCAGACAACCGCCACAACTGTAGTACGGCATCGTTAACACGACTTCAGCAAATATTTTAACATCACAGTGGTTGTGAAGAAATCGGTTGCTTTAAAAAAAGATTGGGTTTTTCCTTGTTTAAGAGTTGTACTGATATCAGTTCTGCACTATGAAATAAAGCTGATGTGACGAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMMVWVTAPVSEGGKLSDVIRGLVPDDLTPQIILQSLNASRHAYRR (SEQ ID NO:188)VRPRGQICIWKVCPPLLQWIHPLVKR Toxin Sequence:Val-Arg-Xaa3-Arg-Gly-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-Cys- (SEQ ID NO:189)Xaa3-Xaa3-Leu-Leu-Gln-Xaa4-Ile-His-Xaa3-Leu-Val-Lys-Arg-{circumflex over( )} Name: Pu14.3 Species: pulicarius Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGATGGTGTGGGTTACAGCGCC (SEQ ID NO:190)TGTGTCTGAAGGTGGTAAATTGAGCGACGTAATTCGGGGTTTGGTGCCAGACGACATAACCCCACAGATTATCTTGCAAAGTCTGAATGCCAGTCGTCATGCTTACAGACCTGTTCGTCTGAGAGGACAGATATGTATCTGGAAGGTATGTCCACCACTACTACAATGGATACATCCATTAGTAAAAAGATGAATGACATCAGACAACCGCCACAACTGTAGTACGACATCGTTAACACGACTTCAGCAAATATTTTAACATCACAGTGGTTGTGAAGAAATCGGTTGCTTTAAAAAAAGATTGGGTTTTTCCTTGTTTAAGAGTTGTACTGATATCAGTTCTGCACTATGAAATAAAGCTGATGTGACGAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMMVWVTAPVSEGGKLSDVIRGLVPDDITPQIILQSLNASRHAYRP (SEQ ID NO:191)VRLRGQICIWKVCPPLLQWIHPLVKR Toxin Sequence:Xaa3-Val-Arg-Leu-Arg-Gly-Gln-Ile-Cys-Ile-Xaa4-Lys-Val- (SEQ ID NO:192)Cys-Xaa3-Xaa3-Leu-Leu-Gln-Xaa4-Ile-His-Xaa3-Leu-Val-Lys- Arg-{circumflexover ( )} Name: Ra14.1 Species: rattus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGGTGGTGGTGGGGTTCACCGTCGG (SEQ ID NO:193)GGGTCACGTCCATCAATCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGACCAGCGCAGGCGACATGAAACCACAACGCCAAAGACGTCTCTGCTGCATCTTTGCCATTCTTTGGTTCTGTTGTCTCGGTTAACAGTACAAATTGCAATGCACTGGCCGATTGAAAGAACTGCAATAAACGGAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMVVVGFTVGGHVHQSHSPTSRSHGDDSIHDKTIHQHLFARLPLENN (SEQ ID NO:194)DDHRSVDLPAGTSAGDMKPQRQRRLCCIFAILWFCCLG Toxin Sequence:Leu-Cys-Cys-Ile-Phe-Ala-Ile-Leu-Xaa4-Phe-Cys-Cys-Leu-# (SEQ ID NO:195)Name: S14.2 Species: striatus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:196)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTCTTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACAACCACAAGAAATGATGAATGACATCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTTAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGRLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:197)SSGAQICIWKVCPPSPWRQPQEMMNDIRQPPQL Toxin Sequence:Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:198)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Gln-Xaa3-Gln-Xaa1-Met-Met-Asn-Asp-Ile-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over( )} Name: Sx14.1 Species: striolatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGACCCTCT (SEQ ID NO:199)GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACGCATCTTAACCCCACAGCATACCTTGCGAAGTCCGACTTCCCTTCTTCGTTCTAACACCGGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACGATCACAAGGAAAAAGATGAATGACGTCAGACAAGCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITDPLSEGGKLNDVIRGLVPRILTPQHTLRSPTSLLRSNTGG (SEQ ID NO:200)SSGAQICIWKVCPPSPWRRSQGKR Toxin Sequence:Ser-Asn-Thr-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:201)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Ser- Gln-# Name: Sx14.2Species: striolatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:202)GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTCTTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACGATCACAAGGAAAAAGATGAATGACGTCAGACAAGCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:203)SSGAQICIWKVCPPSPWRRSQGKR Toxin Sequence:Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:204)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Ser- Gln-# Name: Sx14.3Species: striolatus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:205)GTGTGGATTAAAGACCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTCTTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCAACTGGAAGGTATGTCCACCATCCCCATGGAGACGACCACGAGGAAAATGATGAATGACATCAGACAACCGCCACAACTGTAGTACGACTTCGTTGATACGACTTTAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWIKDPLSEGGKLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:206)SSGAQICNWKVCPPSPWRRPRGK Toxin Sequence:Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Asn- (SEQ ID NO:207)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Xaa3- Arg-# Name:Sx14.4 Species: striolatus Cloned: Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:208)GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTCTTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACAACCACAAGAAATGATGAATGACATCAGACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTTAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACGAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:209)SSGAQICIWKVCPPSPWRQPQEMMNDIRQPPQL Toxin Sequence:Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:210)Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Gln-Xaa3-Gln-Xaa1-Met-Met-Asn-Asp-Ile-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over( )} Name: Sl14.1 Species: sulcatus Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCTCTCT (SEQ ID NO:211)GTCTGAAGGTGGTAAACCGAACGACGTCATTCGGGGTTTTGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAAGGATGTTGGGAAGAGAATGGAATGTTACTGGAAGGCATGTAGACCCACGCTATCGAGACGACATGATCTTGGGTAAAAGATGAATGACGTCAGACAACAGCCACAACTATAGTATGACATCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCGTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAATAAAGCTGATG Translation:MQTAYWVMVMMMVWITASLSEGGKPNDVIRGFVPDDLTPQLILRSLISRRRSDKDV (SEQ ID NO:212)GKRMECYWKACRPTLSRRHDLG Toxin Sequence:Arg-Ser-Asp-Lys-Asp-Val-Gly-Lys-Arg-Met-Xaa1-Cys-Xaa5- (SEQ ID NO:213)Xaa4-Lys-Ala-Cys-Arg-Xaa3-Thr-Leu-Ser-Arg-Arg-His-Asp- Leu-# Name:Tr14.1 Species: terebra Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:214)GTCTGAAGGTGATAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATAACTTAGCCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATCCTCACGGCATTCGTCAGGATGGAGCCCAAATATGTATCTGGAAGATATGTCCACCATCCCCATGGAAACGACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTACGACATCGTTAATACAACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGATGTCATCTCTGCACTGTGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLQSLDSRRHPHGIR (SEQ ID NO:215)QDGAQICIWKICPPSPWKRLGS Toxin Sequence:His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:216)Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Lys-Arg-Leu-Gly-Ser-{circumflex over ( )} Name: Tr14.2 Species: terebra Cloned:Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:217)GTCTGAAGGTGATAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATAACTTAGCCCCACAGCTTGTTTTGCATAGTCTGGATTCCCGTCGTCATCCTCACGGCATTCGTCAGGATGGAGCCCAAATATGTATCTGGAAGATATGTCCACCATCCCCATGGAGACGACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACATCTTGAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCCTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGATGTCATCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLHSLDSRRHPHGIR (SEQ ID NO:218)QDGAQICIWKICPPSPWRRLGS Toxin Sequence:His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:219)Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Leu-Gly-Ser-{circumflex over ( )} Name: Vx14.1 Species: vexillum Cloned:Yes DNA Sequence:GAATTCGCCCTTATGGATCCATGCAGATGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:220)GTGTGGATTAAAGGCCCTGTGTCCGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTGACCCCAGTGTCTGCCTTGCATCATCCGGTTTCCCATCGTCGGTCTCACAGCAGTAGTTTGTGGTGTGTATGTCCATTCAGGGTGTGTCCACCATGCCATGGAAGATGACCTGGTCCCAAACCAACAAAATAACGTCAGACAACCGCCACAACTTTAGTACGACATCCCTTAATACGACTTCAGCAAGTATTTTAACATCACTATGGTGTGATGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGCACTGATAACAGCCCAGCAGTATGAAATAAAGTTGATGTGGCAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQMAYWVMVMMMVWIKGPVSEGGKLNDVIRGLVPDDLTPVSALHHPVSHRRSHSSS (SEQ ID NO:221)LWCVCPFRVCPPCHGR Toxin Sequence:Ser-His-Ser-Ser-Ser-Leu-Xaa4-Cys-Val-Cys-Xaa3-Phe-Arg- (SEQ ID NO:222)Val-Cys-Xaa3-Xaa3-Cys-His-# Name: Vx14.2 Species: vexillum Cloned: YesDNA Sequence: GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG(SEQ ID NO:223) GTGTGGATTACAGCCCCTTTGTCTGAAGGTGGTAAACTGAACGATGTAATTCGGGGTTTCGCGCTAGATGACTTAGCCCAAAGCCGTATTATGCAAAGTCTGGTTTTCAGTCATCAGCCTCTTCCAACGGCATCCATATGTATCTGGAAGATATGTCCACCAGACCCATGGAGACGACATGATCTTCAGAAAAGTAACAAATGACGTCAGACAACCGCCACAACTTGAATACAACATCATTAATACGACTTCAGCAAATATTTTAGCATCACTGTGATTGTTCGGAAGTCAGTTGCTTTAAAAGATTGGATTTGTCCCTGTTGTATTGATGTCAACTCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC Translation:MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGFALDDLAQSRIMQSLVFSHQPLPTA (SEQ ID NO:224)SICIWKICPPDPWRRHDLQKSNKT Toxin Sequence:Ile-Met-Gln-Ser-Leu-Val-Phe-Ser-His-Gln-Xaa3-Leu-Xaa3- (SEQ ID NO:225)Thr-Ala-Ser-Ile-Cys-Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Asp-Xaa3-Xaa4-Arg-Arg-His-Asp-Leu-Gln-Lys-Ser-Asn-Lys-{circumflex over ( )}Name: Vx14.3 Species: vexillum Cloned: Yes DNA Sequence:ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGTTCACCGTCGA (SEQ ID NO:226)GAGTCACGTCCATCAGTCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGACTAGCGCAGGCGACATGAAACCACAACGCCAGAAACGTTTCTGCTGCATCTTTGCCCCGATTCTTTTGTTCTGTTGTTTCGGTTAACAGCACAAATTACACTGCACTGGCCGATTGAAAGAACTGCAATAAACGGTAAAGCAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG Translation:MQTAYWVMVMMMVVGFTVESHVHQSHSPTSRSHGDDSIHDKTIHQHLFARLPLENN (SEQ ID NO:227)DDHRSVDLPAGTSAGDMKPQRQKRFCCIFAPILLFCCFG Toxin Sequence:Phe-Cys-Cys-Ile-Phe-Ala-Xaa3-Ile-Leu-Leu-Phe-Cys-Cys- (SEQ ID NO:228)Phe-#

[0116] TABLE 2 Alignment of β-Superfamily Conotoxins (SEQ ID NO:)* Type2: T14.2 tulipa ----ZTDVLLEATLLTTPAPEQRLFCFWKSCWPRPYPWRRRDLN# (229)M14.1 magus ----ZTDVLLDATLLTTPAPEQRLFCFWKSCWPRPYPWRRRNLN# (230) G14.2geographus ----ZTDVLLEATLLTTPAPEQRLFCFWKSCTWRPYPWRRRDLN# (231) T14.2tulipa -----------------------LFCFWKSCWPRPYPWRRRDLN# (232) M14.1 magus-----------------------LFCFWKSCWPRPYPWRRRNLN# (233) G14.2 geographus-----------------------LFCFWKSCTWRPYPWRRRDLN# (234) Type 3: Ge14.1generalis ----------------SHSSSLWCVCPFRVCPPCH# (235) Vx14.1 vexillum----------------SHSSSLWCVCPFRVCPPCH# (236) Type 4: Fd14.1 flavidus---HDHGIRPKR----------VDICNWRICAPNPLRRHDLKKGNN{circumflex over ( )}(237) Em14.1 emaciatus---HTHGIRPKG----------DGICIWKVCPPDPWRRHRLKKRNN{circumflex over ( )}(238) A14.1 aurisiacus---HTHGIRPKG----------DGICIWKVCPPDPWRRHHLKKRNN{circumflex over ( )}(239) Tr14.1 terebra---HPHGIRQDG----------AQICIWKICPPSPWKRLGS{circumflex over ( )} (240)Tr14.2 terebra ---HPHGIRQDG----------AQICIWKICPPSPWRRLGS{circumflex over( )} (241) Ly14.2 litoglyphus---HPHGIRQDG----------AQICIWKICPPSPWKRLGS{circumflex over ( )} (242)Ly14.1 litoglyphus ---HPHGIRQDG----------AQICIWKICPPSPWRRLGS{circumflexover ( )} (243) Type 5: Cn14.1 consors---DRSDNGGSSG---------AQITCIWKVCPPSP{circumflex over ( )} (244) Cn14.5consors ---DRSDNGGSSG---------AQICIWKVCPPSPWK{circumflex over ( )} (245)Cn14.2 consors ---ARSDNGGSSG---------AQICIWKVCPPSPWRRPQ# (246) Sx14.1striolatus -----SNTGGSSG---------AQICIWKVCPPSPWRRSQ# (247) Sx14.3striolatus -----SNNGRSSG---------AQICNWKVCPPSPWRRPR# (248) Sx14.2striolatus -----SNNGRSSG---------AQICIWKVCPPSPWRRSQ# (249) Sx14.4striolatus-----SNNGRSSG---------AQICIWKVCPPSPWRQPQEMMNDIRQPPQL{circumflex over( )} (250) S14.2 striatus-----SNNGRSSG---------AQICIWKVCPPSPWRQPQEMMNDIRQPPQL{circumflex over( )} (251) A14.3 aurisiacus---LHSDSSDQKG---------AQICIWKVCPPPPWR{circumflex over ( )} (252) A14.2aurisiacus ---LHSDSSDQKGGMNAWTGAGAQICIWKVCPPPPWR{circumflex over ( )}(253) A14.4 aurisiacus ---LRSDSSDQKGGMNASTGAGAQICIWKVCPPSPWRRTQ# (254)Cr14.1 circumcisus ---LRSDSSGQKG---------AQICIWKVCPLSPWRRPQ# (255)Cr14.2 circumcisus---LRSDSSGQKG---------AQICIWKVCPLSPWRRPQGKDE{circumflex over ( )} (256)Ac14.1 achatinus ---LRSDNGGSSG---------AQICIWKVCPPSPWRRPQ# (257) Sm14.1stercusmuscarum ---LGIGSSDQN----------AQICIWKVCPPSP{circumflex over ( )}(258) Cn14.3 consors ---NGSGSSNQKE---------AQLCIWKVCPPSPWR{circumflexover ( )} (259) Cn14.4 consors---NGSGSSNQKE---------AQLCIWKVCPPTPWR{circumflex over ( )} (260) M14.2magus ---NGSGSSNQKE---------AQLCIWKVCPPSPWR{circumflex over ( )} (261)Nb14.2 nobilis ---NGSGSSNQKE---------AQLCIWKVCPPTPWR{circumflex over( )} (262) Type 6: Sl14.1 sulcatus-------------RSDKDVGKRME-CYWKACRPTLSRRHDL# (263) Bk14.1 bocki-------------RSDKDDPGGQE-CYWNVCAPNQGDHMILRKKMNDDRQPPQL{circumflex over( )} (264) Bt14.1 betulinus -------------RSDSDVREV-PVCSWKICPP{circumflexover ( )} (265) Ls14.1 loroisii-------------RSDSDVREVYILCIWKICPPLP{circumflex over ( )} (266) Type 7:Gd14.1 gladiator--------------HPANVRQQGKICVWKVCPPWPVRSPGPQPKNK{circumflex over ( )}(267) Gd14.2 gladiator--------------HPANVRQQGKICVWKVCPPSPVRSPGPLPKNK{circumflex over ( )}(268) Type 8: Ms14.2 musicusGMGPGDLSLQKMFPSLALGPGGDVICRWKVCPPTPWKRLIK{circumflex over ( )} (269)Ms14.3 musicusGMVPGDLALQYLFPSLAFNP-PD-ICTWKVCPPPPWRRPKKITDVGQPPQL{circumflex over ( )}(270) Ms14.1 musicusGMVPGDLVLQYLFPSLAFSP-PD-ICTWKVCPPPPWRRPKKITDVRQPPQL{circumflex over ( )}(271) Ms14.4 musicusGMVPGDLVLQYLFPSLAFNP-PD-ICTWKVCPPPPWRRPKKITDVRQPPQL{circumflex over ( )}(272) Type 9: Mi14.1 miles ZQDQSPHHVCCAIGPVLPFCCVSWLHKLH{circumflex over( )} (273) Mi14.2 miles --------LCCIFAPILWFCCH# (274) Ra14.1 rattus--------LCCIFA-ILWFCCL# (275) Cp14.1 capitaneus -------GFCCDFPPIFWFCCI#(276) Mi14.4 miles ------ZGFCCVVIPILWFCCGGYRTNGTALAD{circumflex over( )} (277) Vx14.3 vexillum --------FCCIFAPILLFCCF# (278) Type 10: Sl14.2sulcatus--------------ZSGCRVPFELKCIWKFCTIYPSRPFASLEEKDECQTVTITVTWDF{circumflexover ( )} (279) Ci14.1 cinereus--------------SSGCSVSLGFKCFWKSCTVIPVRPFVSLEEENECQKVQISAVWGP{circumflexover ( )} (280) Type 11: Pr14.1 parius---------------------PPFSCSGLRGGCVLPPNLRPKFNKG# (281) Pr14.2 parius---------------------PPFSCAGLRGGCVLPPNLRPKFKE# (282) Type 12: Wi14.1wittigi -------------SSDGSDPKAKKQCMWKRCIPDQSR---L-EEDE{circumflex over( )} (283) Ci14.4 cinereus-------------SSDG---KAKKQCAWKTCVPTQWRRRDLKEKDE{circumflex over ( )}(284) Ci14.3 cinereus-------------SSDG---KAKRNCFWKACVPEQWRQRDPKEKDE{circumflex over ( )}(285) Ci14.2 cinereus-------------SSDG---KAKRNCFWKACVPEQWRQRDLKEKDE{circumflex over ( )}(286) Type 13: Nb14.1 nobilis victor-----------FRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY{circumflex over ( )}(287) Nb14.3 nobilis skinneri-----------FRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY{circumflex over ( )}(288) Mi14.3 miles-----------FRPAMQSRSGGMSLCLWKVCPAAPWLVAKRKQETSDY{circumflex over ( )}(289) Miscel- laneous: T14.1 tulipa--------------HFNSVVPTVYICMWKVCPPSP{circumflex over ( )} (290) P14.2purpurascens ------------------ZSEEEKICLWKICPPPPWRRS{circumflex over( )} (291) P14.1 purpurascens------------------ESNGVEICMWKVCPPSPWRRS{circumflex over ( )} (292)Vx14.2 vexillum--------IMQSLVFSHQPLPTASICIWKICPPDPWRRHDLQKSNK{circumflex over ( )}(293) Mu14.1 muriculatus--------IMQSLVFSHQPLPTASICIWKICPPDPWRRHDLQKSNK{circumflex over ( )}(294) Pu14.1 pulicarius------------------VRLRGQICIWKVCPPLLQWIHPLVKR{circumflex over ( )} (295)Pu14.2 pulicarius------------------VRPRGQICIWKVCPPLLQWIHPLVKR{circumflex over ( )} (296)Pu14.3 pulicarius-----------------PVRLRGQICIWKVCPPLLQWIHPLVKR{circumflex over ( )} (297)Mt14.2 mustelinus -----------LVSHTSSKYPGVTFCPWKVCPPAPWRILGV{circumflexover ( )} (298) Ba14.1 baileyi---------------HSDSIILRGLCIWKVCEPPPQR{circumflex over ( )} (299) Pl14.1planorbis --------------SSSNGLKRADLCIHKICPPRYHQSQQ{circumflex over ( )}(300) Lt14.2 litteratus----------HRVFHLDNTYLKIPICAWKVCPPTPWRRRDLKKRNK{circumflex over ( )}(301) Lt14.1 litteratus----SPVSTPYPEFHLDEPYLKIPVCIWKICPPNLLRRRDLKKRNKVRQTTATT{circumflex over( )} (302) Ct14.1 coronatus --------------LSDGRDWTGYICIWKACPRPPWIPPK#(303) Cd14.2 chaldaeus--------------LSEGRNSTVHICMWKVCPPPPWRRPHGQR{circumflex over ( )} (304)CD14.1 chaldaeus --------------LSEGRNSTVHICTWKVCPPPPWRRPHGQR{circumflexover ( )} (305) Eb14.1 ebraeus--------------LSGGTYSRVDTCIWKVCPQSP{circumflex over ( )} (340)

[0117] TABLE 3 Analogs and Truncations of β-Superfamily Conotoxins (SEQID NO:) Q663             ZCMWKRCIPDQSR{circumflex over ( )} (306) F531          VDICNWRICAPNPLR{circumflex over ( )} (307) βG-C1325            LCFX1KSCRPYPWR{circumflex over ( )} (308) βM1           LFCFX1WKSCWPRPYWR{circumflex over ( )} (309) βM2           LFCFX1KSCWPRPYPWR{circumflex over ( )} (310) βM3           LX2CFWKSCWPRPYWR{circumflex over ( )} (311) βM4           LX2CFX1KSCWPRPYWR{circumflex over ( )} (312) βM5           LX2CFWKSCWPR{circumflex over ( )} (313) βM6           LFCFX1KSCWPR{circumflex over ( )} (314) βM7           LX2CFX1KSCWPR{circumflex over ( )} (315) βM8           LX2CFWKSCW{circumflex over ( )} (316) βM9           LFCFX1KSCW{circumflex over ( )} (317) βM10           LX2CFX1KSCW{circumflex over ( )} (318) βM11            FCFX1KSCWPR{circumflex over ( )} (319) βM12            FCFWX3SCWPR{circumflex over ( )} (320) βM13            FCFX1FSCWPR{circumflex over ( )} (321) βM14            FCFWKSCWPR{circumflex over ( )} (322) βP2      ESNGVEICMX1KVCPPSPWRRS{circumflex over ( )} (323) βS1           MECYX1KACRPTLSR{circumflex over ( )} (324) βS12          FELKCIX1KFCTIYPSR{circumflex over ( )} (325) βS12b          FELKCIX1KFCTIYPSRPF{circumflex over ( )} (326) βT          TVYICMX1KVCPPSP{circumflex over ( )} (327) βA-    SDSSDQKAQICIX1KVCPPPPWR{circumflex over ( )} (328) CTL03 βCn2          GAQICIX1KVCPPSPWR{circumflex over ( )} (329) βMs14.5MFPSLALGPGGDVICRX1KVCPPTPWKRLIK{circumflex over ( )} (330) βFd-           VDICNX1RICAPNPLRRRDLKKGNN{circumflex over ( )} (331) F531βF531-            VDICNX1RICAPNPLR{circumflex over ( )} (332) dW βG14.1           RLFCFX1KSCTWRPYPWRRRDLN# (333) βD919SLWCVCPFRVCPPCHGR{circumflex over ( )} (334) [1-4] βD919SLWCVCPFRVCPPCHGR{circumflex over ( )} (335) [2-4] βGe SLWCVCPX2RVCPPCH#(336) [1-4] βGe SLWCVCPX2RVCPPCH# (337) [2-4]

Example 2

[0118] Activity of Type 2 β-Superfamily Conopeptide on Tumor Cell Lines

[0119] Test Substance and Concentration: A β-M14.1 derivative,β-M14.1-D1 (LFCFXKSCWPRPYPWR (SEQ ID NO:309, where X is dW) was used forin vitro anti-tumor studies. The test compound was dissolved and dilutedwith sterile distilled water to obtain initial working solutions of10000, 1000, 100, 10, and 1 μM. In testing, 100-fold dilution was madein culture media to get final assay concentrations of 100, 10, 1, 0.1,and 0.01 μM.

[0120] Cell Culture Media: The culture medium used for the MCF-7 cellline was Minimum Essential Medium, 90%; Fetal Bovine Serum, 10%. Theculture medium used for the MIA PaCa-2 cell line was Dulbecco's ModifiedEagle's Medium, 90%; Fetal Bovine Serum, 10%. All media weresupplemented with 1% Antibiotic-Antimycotic.

[0121] Cell Lines: The cell line MCF-7, which is a breastadenocarcinoma, pleural effusion, human, was obtained from the AmericanType Culture Collection (ATCC HTB-22). The cell line MIA PaCa-2, whichis a pancreatic carcinoma, human, was obtained form the American Typeculture Collection (ATCC CRL-1420). The tumor cells were incubated in anair atmosphere of 5% CO₂ at 3° C.

[0122] Chemicals: The sources of the chemicals were as follows:AlamarBlue (Biosource, USA), Antibiotic-Antimycotic (GIBCO BRL, USA),Dulbecco's Modified Eagle's Medium (GIBCO BRL, USA), Fetal Bovine Serum(HyClone, USA), Minimum Essential medium (GIBCO BRL, USA) and Mitomycin(Kyowa, Japan).

[0123] Equipment: Centrifuge 5810R (Eppendorf, Germany), CO₂ Incubator(Forma Scientific Inc., USA), Hemacytometer(Hausser Scientific Horsham,USA), Inverted Microscope CK-40 (Olympus, Japan), Spectrafluor Plus(Tecan, Austria), System Microscope E-400 (Nikon, Japan) and VerticalLaminar Flow (Tsao-Hsin, Taiwan).

[0124] Reference Methods: Ahmed et al. (1994), Boyd et al. (1989), Boydet al. (1992).

[0125] Aliquots of 100 μl of cell suspension (about 2.5×10³/well) wereplaced in 96-well microtiter plates in an air atmosphere of 5% CO₂ at37° C. After 24 hours, 100 μl of growth medium and 2 μl of testsolution, or mitomycin or vehicle (sterile distilled water), were addedrespectively per well in duplicate for an additional 72-hour incubation.The test compound, β-M14.1 derivative, was evaluated at concentrationsof 100, 10, 1, 0.1 and 0.01 μM. At the end of incubation, the media inmicroplate were all removed, and then 200 μl of fresh media and 20 μl of90% alamarBlue reagent were added to each well for another 6-hourincubation before detection of cell viability by fluorescent intensity.Fluorescent intensity was measured using a Spectraflour Plus platereader with excitation at 530 nm and emission at 590 nm.

[0126] The measured results was calculated by the following formula:

PG (%)=100×(Mean F _(test) −Mean F _(time0))/(Mean F _(ctrl) −Mean F_(time0))

If (Mean F _(test) −Mean F _(time0))<0, then PG (%)=100×(Mean F _(test)−Mean F _(time0))/(Mean F _(time0) −Mean F _(blank))

[0127] Where:

[0128] PG: percent growth

[0129] Mean F_(time0)=The average of 2 measured fluorescent intensitiesof reduced alamarBlue at the time just before exposure of cells to thetest substance.

[0130] Mean F_(test)=The average of 2 measured fluorescent intensitiesof alamarBlue after 72-hour exposure of cells to the test substance.

[0131] Mean F_(ctrl)=The average of 2 measured fluorescent intensitiesof alamarBlue after 72-hour incubation without the test substance.

[0132] Mean F_(blank)=The average of 2 measured fluorescent intensitiesof alamarBlue in medium without cells after 72-hour incubation.

[0133] A decrease of 50% or more (≧50%) in fluorescent intensityrelative to vehicle-treated control indicated significant growthinhibition, cytostatic or cytotoxic activity, and a semi-quantitativeIC₅₀, TGI and LC₅₀ were then determined by nonlinear regression usingGraphPad Prism (GraphPad Software, USA).

[0134] The assays were used to detect changes in cell proliferationbased on the ability of viable cells to cause alamarBlue to change fromits oxidized (non-fluorescent, blue) to a reduced (fluorescent, red)form. With the results obtained from the alamarBlue reaction, cellproliferation can be quantified and metabolic activity of viable cellscan be examined. The β-M14.1-D1 was tested for its effect upon theproliferation of 2 different human tumor cell lines, MCF-7 (breast) andMIA PaCa-2 (pancreas), at five final assay concentrations from 0.01 to100 μM through serial 10-fold dilutions.

[0135] Based on the results obtained, the β-M14.1-D1 exhibitedsignificant growth inhibition (≧50%) relative to the respective vehicletreated control group at concentrations between 10 μM to 100 μM in the 2human tumor cells lines (Table 4). Significant activity was observed forthe concurrently tested standard reference agent Mitomycin at <10 μM(Table 1). Consequently, semi-quantitative determinations of estimatedIC₅₀ (50% inhibition concentration), TGI (total growth inhibition) andLC₅₀ (50% lethal concentration) by nonlinear regression analysis werecalculated (Table 5). TABLE 4 Effect of Test Substance Tumor CellsPercent Growth (Mean ± SEM, n = 2) Concentration (μM) Treatment AssayName Blank Time₀ Vehicle 100 10 1 0.1 0.01 0.001 PT# 1018911-ADD 370000Breast, −100 0 100 −43 ± 11 102 ± 14  87 ± 9  88 ± 12 100 ± 18 ^(a) _(—)β-M14.1-D1 MCF-7 Mitomycin 370000 Breast, −100 0 100 — −96 ± 0 −38 ± 16 5 ± 12  88 ± 8  95 ± 7 MCF-7 PT# 1018911-ADD 371700 Pancreas, −100 0100 −14 ± 9 109 ± 2 100 ± 4 102 ± 6 102 ± 3 — β-M14.1-D1 MIA PaCa-2Mitomycin 371700 Pancreas, −100 0 100 — −93 ± 2 −44 ± 16  1 ± 6  76 ± 5105 ± 10 MIA PaCa-2

[0136] TABLE 5 Estimated IC₅₀, TGI and LC₅₀ Values Treatment Prot. #Assay Name ^(a)IC₅₀ ^(b)TGI ^(c)LC₅₀ PT# 1018911-ADD 370000 Tumor,Breast, MCF-7   62 μM   81 μM  >100 μM β-M14.1-D1 Mitomycin 370000Tumor, Breast, MCF-7 0.035 μM 0.18 μM   0.93 μM PT# 1018911-ADD 371700Tumor Pancreas,   79 μM   95 μM  >100 μM β-M14.1-D1 MIA PaCa-2 Mitomycin371700 Tumor Pancreas, 0.028 μM 0.15 μM   0.78 μM MIA PaCa-2

EXAMPLE 3 In Vitro Functional Activity of Type 2 β-SuperfamilyConopeptide

[0137] The in vitro functional activity of β-M14.1-D1 with respect tosomatostatin sst₂ and sst₅ was tested using the following assays.Somatostatin sst₂ (Feniuk et al., 1993) Tissue: Duncan Hartley Guineapig 325 ± 25 g Vehicle: 0.1 mL Distilled Water Incubation Time/Temp: 5minutes @ 32° C. Incubation Buffer: Krebs, pH 7.4 Administration Volume:10 μL Bath Volume:  10 mL Time of Assessment: 5 minutes QuantitationMethod: Isometric (gram changes) Significance Criteria-Ag: ≧50%Inhibition of contraction relative to somatostatin₂₈-responsesSignificance Criteria-Ant: ≧50% Inhibition of somatostatin₂₈ relaxantresponse Somatostatin sst₅ (Feniuk et al., 1993) Tissue: Duncan HartleyGuinea pig 325 ± 25 g Vehicle: 0.1 mL Distilled Water IncubationTime/Temp: 5 minutes @ 32° C. Incubation Buffer: Krebs, pH 7.4Administration Volume: 10 μL Bath Volume:  10 mL Time of Assessment: 5minutes Quantitation Method: Isometric (gram changes) SignificanceCriteria-Ag: ≧50% Inhibition of contraction relative tosomatostatin₂₈-responses Significance Criteria-Ant: ≧50% Inhibition ofsomatostatin₂₈ relaxant response

[0138] Biochemical assay results are presented as the percent inhibitionof specific binding or activity. All other results are expressed interms of that assay's quantitation method. For primary assays, only thelowest concentration with a significant response judged by the assays'criteria, is shown. Primary screening in duplicate with quantitativedata are shown where applicable for individual assays. Significantresponses were noted in the primary assays shown in Table 6. TABLE 6Primary Tests^(a) Primary Tissue Assay Tissue, gp Conc. Criteria AG ANTEC₅₀/IC₅₀ Somatostatin ileum 1 μM ≧50% 68% ND 0.49 μM sst₂ Somatostatinvas deferens 1 μM ≧50% 61% ND 0.59 μM sst₅

EXAMPLE 4 Radioligand Binding Assay of Type 2 β-Superfamily Conopeptide

[0139] The radioligand binding activity of β-M14.1-D1 with respect tosomatostatin sst₁, sst₂, sst₃ and sst₄ and sst₅ was tested using thefollowing assays. Somatostatin sst₁ (Liapakis et al., 1996; Patel andSrikant, 1994) Source: Human recombinant CHO-K1 Ligand: 0.1 nM ¹²⁵ISomatostatin-14 Vehicle: 0.4% DMSO Incubation Time/Temp: 2 hours @ 25°C. Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mM MgCl₂, 1 mM CaCl₂, 0.5%BSA NonSpecific Ligand: 1 μM Somatostatin-14 K_(d): 1.9 nM (historicalvalue) B_(max): 0.5 pmol/mg Protein (historical value) Specific Binding:60% (historical value) Quantitation Method: Radioligand BindingSignificance Criteria: ≧50% of max stimulation or inhibitionSomatostatin sst₂ (Patel and Srikant, 1994) Source: Human recombinantCHO-K1 Ligand: 0.03 nM ¹²⁵I Somatostatin-14 Vehicle: 1% H₂O IncubationTime/Temp: 4 hours @ 25° C. Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mMMgCl₂, 1 mM CaCl₂, 0.5% BSA NonSpecific Ligand: 1 μM Somatostatin-14K_(d): 0.034 nM (historical value) B_(max): 11 pmol/mg Protein(historical value) Specific Binding: 90% (historical value) QuantitationMethod: Radioligand Binding Significance Criteria: ≧50% of maxstimulation or inhibition Somatostatin sst₃ (Liapakis et al., 1996;Patel and Srikant, 1994) Source: Human recombinant CHO-K1 Ligand: 0.1 nM¹²⁵I Somatostatin-14 Vehicle: 0.4% DMSO Incubation Time/Temp: 2 hours @25° C. Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mM MgCl₂, 1 mM CaCl₂,0.5% BSA NonSpecific Ligand: 1 μM Somatostatin-14 K_(d): 0.79 nM(historical value) B_(max): 1.1 pmol/mg Protein (historical value)Specific Binding: 78% (historical value) Quantitation Method:Radioligand Binding Significance Criteria: ≧50% of max stimulation orinhibition Somatostatin sst₄ (Patel and Srikant, 1994) Source: Humanrecombinant CHO-K1 Ligand: 0.12 nM ¹²⁵I Somatostatin-14 Vehicle: 0.4%DMSO Incubation Time/Temp: 2 hours @ 25° C. Incubation Buffer: 25 mMHepes, pH 7.4, 5 mM MgCl₂, 1 mM CaCl₂, 0.5% BSA NonSpecific Ligand: 1 μMSomatostatin-14 K_(d): 0.87 nM (historical value) B_(max): 0.5 pmol/mgProtein (historical value) Specific Binding: 60% (historical value)Quantitation Method: Radioligand Binding Significance Criteria: ≧50% ofmax stimulation or inhibition Somatostatin sst₅ (Greenwood et al., 1997;Patel and Srikant, 1994) Source: Human recombinant HEK-293 EBNA cellsLigand: 0.1 nM ¹²⁵I Somatostatin-14 Vehicle: 1% H₂O IncubationTime/Temp: 60 minutes @ 37° C. Incubation Buffer: 50 mM Hepes, pH 7.4, 5mM MgCl₂, 1 mM CaCl_(2, 0.5% BSA) NonSpecific Ligand: 1 μMSomatostatin-14 K_(d): 0.5 nM (historical value) B_(max): 1.2 pmol/mgProtein (historical value) Specific Binding: 94% (historical value)Quantitation Method: Radioligand Binding Significance Criteria: ≧50% ofmax stimulation or inhibition

[0140] Biochemical assay results are presented as the percent inhibitionof specific binding or activity. All other results are expressed interms of that assay's quantitation method. For primary assays, only thelowest concentration with a significant response judged by the assays'criteria, is shown. Primary screening in duplicate with quantitativedata (e.g., IC₅₀±SEM, K_(i)±SEM and nH) are shown where applicable forindividual assays. In screening packages, primary screening in duplicatewith semi-quantitative data (e.g., estimated IC₅₀, K_(i) and nH) areshown where applicable (concentration range of 4 log units). Significantresponses were noted in the primary assays shown in Table 7. TABLE 7Primary Test Primary Biochemical % Assay Species Conc. Inh. IC₅₀ K_(i)n_(h) Somatostatin hum 0.1 μM 61 0.053 μM 0.05 μM 0.736 sst₁Somatostatin hum 0.1 μM 90 0.018 μM 9.35 nM 1.24 sst₂ Somatostatin hum 10 nM 61  6.14 nM 5.45 nM 0.714 sst₃ Somatostatin hum  10 μM 67  5.63μM 4.95 μM 1.26 sst₄ Somatostatin hum 0.1 μM 61 0.082 μM 0.068 μM  0.961sst₅

EXAMPLE 5 Radioligand Binding Assay of β-Superfamily Conopeptides

[0141] The radioligand binding activity of truncations of β-M14.1-D1 andother β-superfamily conopeptides with respect to somatostatin sst₁,sst₂, sst₃ and sst₄ and sst₅ was tested as described in Example 4. Thepeptides which were tested are set forth in Table 8. The significantresponsers (≧50% inhibition or stimulation) are set forth in Table 9.TABLE 8 Conopeptide Type Sequence (SEQ ID NO:)^(a) β-M14.1-6 2LFCFX₁KSCWPR{circumflex over ( )} (314) β-M14.1-9 2LFCFX₁KSCW{circumflex over ( )} (317) β-M14.1-10 2LX₂CFX₁KSCW{circumflex over ( )} (318) β-T14.1-D1 MiscTVYICMX₁KVCPPSP{circumflex over ( )} (327) β-Sl14.1-D1 6MECYX₁KACRPTLSR{circumflex over ( )} (324) β-Cn14.2-D1 5GAQICIX₁KVCPPSPWR{circumflex over ( )} (329)

[0142] TABLE 9 Primary Test Primary Biochemical Assay Species PeptideConc. % Inh. Somatostatin sst₁ hum β-Cn14.2-D1  10 μM 61 Somatostatinsst₃ hum β-M14.1-6 0.1 μM 63 Somatostatin sst₃ hum β-M14.1-9 0.1 μM 72Somatostatin sst₃ hum β-Sl14.1-D1  10 μM 82 Somatostatin sst₃ humβ-Cn14.2-D1  10 μM 84 Somatostatin sst₄ hum β-Cn14.2-D1  10 μM 60Somatostatin sst₅ hum β-M14.1-6 0.1 μM 57 Somatostatin sst₅ humβ-M14.1-9 0.1 μM 55 Somatostatin sst₅ hum β-M14.1-10 0.1 μM 65Somatostatin sst₅ hum β-T14.1-D1  10 μM 65 Somatostatin sst₅ humβ-Sl14.1-D1  10 μM 86 Somatostatin sst₅ hum β-Cn14.2-D1  12 μM 56

EXAMPLE 6 Radioligand Binding Assay of Type 3 β-Superfamily Conopeptide

[0143] The radioligand binding activity of P-Gel4.1 D1(SLWCVCPFRVCPPCH#; SEQ ID NO:335 with 1-3 fold), D919 (with 1-4 fold,SEQ ID NO:334) and D919 (with 2-4 fold, SEQ ID NO:335) with respect tomelanocortin MC₃, MC₄, MC₅ and MCH (h) was tested using the followingassays. Melanocortin MC₃ (Schioth et al., 1995) Source: Humanrecombinant HEK-293 cells Ligand: 0.035 nM ¹²⁵I NDP-αMSH Vehicle: 0.4%DMSO Incubation Time/Temp: 60 min @ 37° C. Incubation Buffer: 25 mMHEPES-KOH, 0.2% BSA, pH 7.0, 100 mM NaCl, 1 mM 1,10-phenanthroline, 1.5mM CaCl2, 1 mM MgSO4, and one complete protease inhibitor tablet/ 100 mlNonSpecific Ligand: 3 μM NDP-αMSH K_(d): 0.53 nM (historical value)B_(max): 6 pmol/mg Protein (historical value) Specific Binding: 85%(historical value) Quantitation Method: Radioligand Binding SignificanceCriteria: ≧50% of max stimulation or inhibition Melanocortin MC₄(Schioth et al., 1995) Source: Human recombinant HEK-293 cells Ligand:0.02 nM ¹²⁵I NDP-αMSH Vehicle: 01% H₂0 Incubation Time/Temp: 2 hours @37° C. Incubation Buffer: 25 mM-HEPES-KOH, 0.2% BSA, pH 7.0, 100 mMNaCl, 1 mM 1,10-phenanthroline, 1.5 mM CaCl2, 1 mM MgSO4, and onecomplete protease inhibitor tablet/ 100 ml NonSpecific Ligand: 3 μMNDP-αMSH K_(d): 0.5 nM (historical value) B_(max): 3.9 pmol/mg Protein(historical value) Specific Binding: 90% (historical value) QuantitationMethod: Radioligand Binding Significance Criteria: ≧50% of maxstimulation or inhibition Melanocortin MC₅ (Schioth et al., 1995)Source: Human recombinant HEK-293 cells Ligand: 0.035 nM ¹²⁵I NDP-αMSHVehicle: 1% H₂0 Incubation Time/Temp: 2 hours @ 37° C. IncubationBuffer: 25 mM HEPES-KOH, 0.2% BSA, pH 7.0, 100 mM NaCl, 1 mM1,10-phenanthroline, 1.5 mM CaCl2, 1 mM MgSO4, and one complete proteaseinhibitor tablet/ 100 ml NonSpecific Ligand: 3 μM NDP-αMSH K_(d): 0.53nM (historical value) B_(max): 6 pmol/mg Protein (historical value)Specific Binding: 85% (historical value) Quantitation Method:Radioligand Binding Significance Criteria: ≧50% of max stimulation orinhibition MCH (h) (Chambers et al., 1999) Source: Human recombinant CHOcells Ligand: 0.1 nM ¹²⁵I [Phe¹³, Tyr¹⁹]-MCH Incubation Time/Temp: 60min @ 22° C. NonSpecific Ligand: 1 μM NDP-αMSH K_(d): 0.05 nM(historical value) Quantitation Method: Radioligand Binding SignificanceCriteria: ≧50% of max stimulation or inhibition Melanocortin MC₁(Siegrist et al., 1988) Source: Human recombinant CHO cells Ligand: 0.05nM ¹²⁵I NDP-αMSH Incubation Time/Temp: 90 min @ 22° C. NonSpecificLigand: 0.1 μM MCH K_(d): 0.62 nM (historical value) QuantitationMethod: Radioligand Binding Significance Criteria: ≧50% of maxstimulation or inhibition

[0144] Biochemical assay results are presented as the percent inhibitionof specific binding or activity. All other results are expressed interms of that assay's quantitation method. For primary assays, only thelowest concentration with a significant response judged by the assays'criteria, is shown. Primary screening in duplicate with quantitativedata (e.g., IC₅₀±SEM, K_(i)±SEM and nH) are shown where applicable forindividual assays. In screening packages, primary screening in duplicatewith semi-quantitative data (e.g., estimated IC₅₀, K_(i) and nH) areshown where applicable (concentration range of 4 log units). Significantresponses were noted in the primary assays shown in Tables 10 and 11.TABLE 10 Primary Test for β-Ge14.1-D1 Primary Biochemical Assay SpeciesConc. % Inh. IC₅₀ K_(i) n_(h) Melanocortin hum 1 μM 71 0.294 μM 0.276 μM0.762 MC₅

[0145] TABLE 11 Primary Test Primary Biochemical Assay Species PeptideConc. % Inh. Melanocortin MC₃ hum D919 [2, 4] 10 μM 67 Melanocortin MC₄hum D919 [2, 4] 10 μM 67 Melanocortin MC₄ hum D919 [1, 4] 10 μM 58Melanocortin MC₅ hum D919 [2, 4] 10 μM 96 Melanocortin MC₅ hum D919 [1,4] 10 μM 89 Melanocortin MC₁ hum D919 [2, 4] 10 μM 60 Melanocortin MC₁hum D919 [1, 4] 10 μM 66 MCH (h) hum D919 [2, 4] 10 μM 83 MCH (h) humD919 [1, 4] 10 μM 65

[0146] It will be appreciated that the methods and compositions of theinstant invention can be incorporated in the form of a variety ofembodiments, only a few of which are disclosed herein. It will beapparent to the artisan that other embodiments exist and do not departfrom the spirit of the invention. Thus, the described embodiments areillustrative and should not be construed as restrictive.

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1 340 1 456 DNA Conus flavidus CDS (7)..(255) 1 ggatcc atg cag acg gcctac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp ValMet Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggtaaa ttg aac gac gta att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly LysLeu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca gat gac tta acc ccacag ctt att ttg caa agt ctg 144 Gly Leu Val Pro Asp Asp Leu Thr Pro GlnLeu Ile Leu Gln Ser Leu 35 40 45 gat tcc cgt cgt cat gat cac ggc att cgtccg aag aga gtc gac ata 192 Asp Ser Arg Arg His Asp His Gly Ile Arg ProLys Arg Val Asp Ile 50 55 60 tgt aac tgg agg ata tgt gca cca aac cca ttgaga cga cat gat ctt 240 Cys Asn Trp Arg Ile Cys Ala Pro Asn Pro Leu ArgArg His Asp Leu 65 70 75 aag aaa gga aac aat tgacgtcaga caaccgccacaacttgagta cgacatcgtt 295 Lys Lys Gly Asn Asn 80 aatacgactt cagcaaatatgaaattttca gcatcactgt ggttgtgaag aaatcagttg 355 ctttaaaagg ttggatttgtccttgtttaa gccgttgtac tgatgacatc tctgcactat 415 gaaataaagc tgatgtgacaaactaaaaaa aaaaaaaaaa a 456 2 83 PRT Conus flavidus 2 Met Gln Thr AlaTyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro LeuSer Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro AspAsp Leu Thr Pro Gln Leu Ile Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg HisAsp His Gly Ile Arg Pro Lys Arg Val Asp Ile Cys Asn 50 55 60 Trp Arg IleCys Ala Pro Asn Pro Leu Arg Arg His Asp Leu Lys Lys 65 70 75 80 Gly AsnAsn 3 33 PRT Conus flavidus PEPTIDE (1)..(33) Xaa at residues 7, 20 and22 may be Pro or hydroxy-Pro; Xaa at residue 15 may be Trp (Dor L) orbromo-Trp (Dor L) 3 His Asp His Gly Ile Arg Xaa Lys Arg Val Asp Ile CysAsn Xaa Arg 1 5 10 15 Ile Cys Ala Xaa Asn Xaa Leu Arg Arg His Asp LeuLys Lys Gly Asn 20 25 30 Asn 4 374 DNA Conus miles CDS (7)..(315) 4ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg gtg 48 MetGln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val 1 5 10 ggg ctc accgtc ggg agt cac gtc cat cgg tct cac agt cct aca tcg 96 Gly Leu Thr ValGly Ser His Val His Arg Ser His Ser Pro Thr Ser 15 20 25 30 cgc agc catggt gat gac tcc att cat gac aag acg att cat caa cat 144 Arg Ser His GlyAsp Asp Ser Ile His Asp Lys Thr Ile His Gln His 35 40 45 ctg ttt gcc cgtctt cct ctg gag aac aac gac gac cat cgt tct gtg 192 Leu Phe Ala Arg LeuPro Leu Glu Asn Asn Asp Asp His Arg Ser Val 50 55 60 gat ctt cct gca gggaat ggt gca ggc aac acc aag caa caa gac caa 240 Asp Leu Pro Ala Gly AsnGly Ala Gly Asn Thr Lys Gln Gln Asp Gln 65 70 75 agt cct cat cat gtg tgttgt gct att ggt ccg gtt ctt cca ttc tgt 288 Ser Pro His His Val Cys CysAla Ile Gly Pro Val Leu Pro Phe Cys 80 85 90 tgt gtc agt tgg ctg cac aaactc cat tgaactggcc aatgaaaata 335 Cys Val Ser Trp Leu His Lys Leu His 95100 actcaggaat agacagaaag gcaaaaaaaa aaaaaaaaa 374 5 103 PRT Conus miles5 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Leu 1 5 1015 Thr Val Gly Ser His Val His Arg Ser His Ser Pro Thr Ser Arg Ser 20 2530 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 4045 Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 5560 Pro Ala Gly Asn Gly Ala Gly Asn Thr Lys Gln Gln Asp Gln Ser Pro 65 7075 80 His His Val Cys Cys Ala Ile Gly Pro Val Leu Pro Phe Cys Cys Val 8590 95 Ser Trp Leu His Lys Leu His 100 6 29 PRT Conus miles PEPTIDE(1)..(29) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 6, 15 and18 may be Pro or hydroxy-Pro; Xaa at residue 24 may be Trp (D or L) orbromo-Trp (D or L) 6 Xaa Gln Asp Gln Ser Xaa His His Val Cys Cys Ala IleGly Xaa Val 1 5 10 15 Leu Xaa Phe Cys Cys Val Ser Xaa Leu His Lys LeuHis 20 25 7 359 DNA Conus miles CDS (7)..(291) 7 ggatcc atg cag acg gcctac tgg gtg atg gtg atg atg atg gtg gtg 48 Met Gln Thr Ala Tyr Trp ValMet Val Met Met Met Val Val 1 5 10 ggg ttc acc gtc ggg ggt cac gtc catcgg tct cac agt cct aca tcg 96 Gly Phe Thr Val Gly Gly His Val His ArgSer His Ser Pro Thr Ser 15 20 25 30 cgc agc cat ggt gat gac tcc att catgac aag acg att cat caa cat 144 Arg Ser His Gly Asp Asp Ser Ile His AspLys Thr Ile His Gln His 35 40 45 ctg ttt gcc cgt ctt cct cag gag aac aacgac gac cat cgt tct gtg 192 Leu Phe Ala Arg Leu Pro Gln Glu Asn Asn AspAsp His Arg Ser Val 50 55 60 gat ctt cct gca ggg act agc gca ggc gac atgaaa cca caa cgc caa 240 Asp Leu Pro Ala Gly Thr Ser Ala Gly Asp Met LysPro Gln Arg Gln 65 70 75 aga cgt ctc tgc tgc atc ttt gcc ccg att ctt tggttc tgt tgt cac 288 Arg Arg Leu Cys Cys Ile Phe Ala Pro Ile Leu Trp PheCys Cys His 80 85 90 ggt taacagctca aattacactg cactggccga ttgaaagaactgcaataaac 341 Gly 95 ggaaaaaaaa aaaaaaaa 359 8 95 PRT Conus miles 8 MetGln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15Thr Val Gly Gly His Val His Arg Ser His Ser Pro Thr Ser Arg Ser 20 25 30His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45Ala Arg Leu Pro Gln Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Arg 65 70 7580 Leu Cys Cys Ile Phe Ala Pro Ile Leu Trp Phe Cys Cys His Gly 85 90 959 14 PRT Conus miles PEPTIDE (1)..(14) Xaa at residue 7 may be Pro orhydroxy-Pro; Xaa at residue 10 may be Trp (D or L) or bromo-Trp (D or L)9 Leu Cys Cys Ile Phe Ala Xaa Ile Leu Xaa Phe Cys Cys His 1 5 10 10 351DNA Conus capitaneus CDS (7)..(291) 10 ggatcc atg cag acg gcc tac tgggtg atg gtg atg atg atg gtg gtg 48 Met Gln Thr Ala Tyr Trp Val Met ValMet Met Met Val Val 1 5 10 ggg ttc acc gtc ggg ggt cac gtc cat cgg tctcac agt cct aca tcg 96 Gly Phe Thr Val Gly Gly His Val His Arg Ser HisSer Pro Thr Ser 15 20 25 30 cgc agc cat ggt gat gac tcc att cat gac gagacg att cat caa cat 144 Arg Ser His Gly Asp Asp Ser Ile His Asp Glu ThrIle His Gln His 35 40 45 ctg ttt gcc cgt ctt cct cag gag aac aac gac gaccat cgt tct gtg 192 Leu Phe Ala Arg Leu Pro Gln Glu Asn Asn Asp Asp HisArg Ser Val 50 55 60 gat ctt cct gca ggg act agc gca ggc gac atg aaa ccacaa cgc caa 240 Asp Leu Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro GlnArg Gln 65 70 75 aga ggt ttc tgc tgc gac ttt ccc ccg att ttt tgg ttc tgttgt atc 288 Arg Gly Phe Cys Cys Asp Phe Pro Pro Ile Phe Trp Phe Cys CysIle 80 85 90 ggt taacagcaca aattacactg cactggccga ttgaaagaac tgcaataaac341 Gly 95 ggaaaaaaaa 351 11 95 PRT Conus capitaneus 11 Met Gln Thr AlaTyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 Thr Val GlyGly His Val His Arg Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly AspAsp Ser Ile His Asp Glu Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg LeuPro Gln Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala GlyThr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Gly 65 70 75 80 Phe CysCys Asp Phe Pro Pro Ile Phe Trp Phe Cys Cys Ile Gly 85 90 95 12 15 PRTConus capitaneus PEPTIDE (1)..(15) Xaa at residues 7 and 8 may be Pro orhydroxy-Pro; Xaa at residue 11 may be Trp (D or L) or bromo-Trp (D or L)12 Gly Phe Cys Cys Asp Phe Xaa Xaa Ile Phe Xaa Phe Cys Cys Ile 1 5 10 1513 348 DNA Conus generalis CDS (7)..(222) 13 ggatcc atg cag acg gcc tactgg gta atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val MetVal Met Met Met Val Trp 1 5 10 att aaa ggc cct gtg tct gaa ggt ggt aaattg aac gac gta att cgg 96 Ile Lys Gly Pro Val Ser Glu Gly Gly Lys LeuAsn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca gac gac ttg acc cca gtgttt gcc ttg cat cat ccg 144 Gly Leu Val Pro Asp Asp Leu Thr Pro Val PheAla Leu His His Pro 35 40 45 gtt tcc cat cgt cgg tct cac agc agt agt ttgtgg tgt gta tgt cca 192 Val Ser His Arg Arg Ser His Ser Ser Ser Leu TrpCys Val Cys Pro 50 55 60 ttc agg gtg tgt cca cca tgc cat gga agatgacctggtc ccaaaccaac 242 Phe Arg Val Cys Pro Pro Cys His Gly Arg 65 70aaaataacgt cagacaaccg ccacaacttt agtacgacat cccttaatac gacttcagca 302agtattttaa catcactatg gtgtgatgaa atcagttgct ttaaaa 348 14 72 PRT Conusgeneralis 14 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp IleLys 1 5 10 15 Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp Val Ile ArgGly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Val Phe Ala Leu His His ProVal Ser 35 40 45 His Arg Arg Ser His Ser Ser Ser Leu Trp Cys Val Cys ProPhe Arg 50 55 60 Val Cys Pro Pro Cys His Gly Arg 65 70 15 19 PRT Conusgeneralis PEPTIDE (1)..(19) Xaa at residue 7 may be Trp (D or L) orbromo-Trp (D or L); Xaa at residues 11, 16 and 17 may be Pro orhydroxy-Pro 15 Ser His Ser Ser Ser Leu Xaa Cys Val Cys Xaa Phe Arg ValCys Xaa 1 5 10 15 Xaa Cys His 16 405 DNA Conus wittigi CDS (1)..(210)misc_feature (1)..(405) n may be any base 16 atg atg ttg gtg tgg att acagcc cct ctg cct gaa ggt ggt aaa ctg 48 Met Met Leu Val Trp Ile Thr AlaPro Leu Pro Glu Gly Gly Lys Leu 1 5 10 15 aag cac gta att cgg ggt ttggtg cca gac gac tta acc cca cag ctt 96 Lys His Val Ile Arg Gly Leu ValPro Asp Asp Leu Thr Pro Gln Leu 20 25 30 atc ttg cga agt ctg att tcc cgtcgt agt tct gac ggc agt gat ccg 144 Ile Leu Arg Ser Leu Ile Ser Arg ArgSer Ser Asp Gly Ser Asp Pro 35 40 45 aag gca aaa aaa cag tgt atg tgg aagaga tgt ata cca gac caa tcg 192 Lys Ala Lys Lys Gln Cys Met Trp Lys ArgCys Ile Pro Asp Gln Ser 50 55 60 aga cta gaa gaa gat gaa tgatgtcagacaaccgccat cactgtagta 240 Arg Leu Glu Glu Asp Glu 65 70 tgacatcgttaatacgactt aagcaaatat tttaacatca ctgtggttct gaagacatca 300 gttgctttaaaagattggat tcttccttgt ttaagagttg tactganatc attcctgccc 360 tgtgaaataaagctgatgtt gacanncaaa caaaaaaaaa aaaaa 405 17 70 PRT Conus wittigimisc_feature (1)..(405) n may be any base 17 Met Met Leu Val Trp Ile ThrAla Pro Leu Pro Glu Gly Gly Lys Leu 1 5 10 15 Lys His Val Ile Arg GlyLeu Val Pro Asp Asp Leu Thr Pro Gln Leu 20 25 30 Ile Leu Arg Ser Leu IleSer Arg Arg Ser Ser Asp Gly Ser Asp Pro 35 40 45 Lys Ala Lys Lys Gln CysMet Trp Lys Arg Cys Ile Pro Asp Gln Ser 50 55 60 Arg Leu Glu Glu Asp Glu65 70 18 29 PRT Conus wittigi PEPTIDE (1)..(29) Xaa at residues 7 and 20may be Pro or hydroxy-Pro; Xaa at residue 15 may be Trp (D or L) orbromo-Trp (D or L); Xaa at residues 26, 27 and 29 may be Glu or Gla 18Ser Ser Asp Gly Ser Asp Xaa Lys Ala Lys Lys Gln Cys Met Xaa Lys 1 5 1015 Arg Cys Ile Xaa Asp Gln Ser Arg Leu Xaa Xaa Asp Xaa 20 25 19 463 DNAConus consors CDS (7)..(222) 19 ggatcc atg cag acg gcc tac tgg gtg atggtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met MetMet Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gacgta att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp ValIle Arg 15 20 25 30 ggt ttg gtg tca cac atc tta atc cca cag cat acc ttgcga agt ctg 144 Gly Leu Val Ser His Ile Leu Ile Pro Gln His Thr Leu ArgSer Leu 35 40 45 act tcc cgt gat cgt tct gac aac ggt ggt tcg agt gga gcacaa ata 192 Thr Ser Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala GlnIle 50 55 60 tgc atc tgg aag gta tgt cca cca tcc cca tagagacgaccacgaggaaa 242 Cys Ile Trp Lys Val Cys Pro Pro Ser Pro 65 70 aagatgaacggcgtcagaca accgccacaa ctgtagtacg acatcgttga tacgacttca 302 gcaactattttaacatcact gtggttgtga agaaatcagt cgctttaaaa gattggattt 362 ttccttgtttaagagttgta ctgatatcag ctctgcacta tgaaataaag ctgatgtgac 422 ataaaaaaaaaaaaaaaaag tactctgcgt tgttactcga g 463 20 72 PRT Conus consors 20 MetGln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu Thr Ser 35 40 45Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60Trp Lys Val Cys Pro Pro Ser Pro 65 70 21 23 PRT Conus consors PEPTIDE(1)..(23) Xaa at residue 16 may be Trp (D or L) or bromo-Trp (D or L);Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 21 Asp Arg SerAsp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys ValCys Xaa Xaa Ser Xaa 20 22 470 DNA Conus consors CDS (7)..(246) 22 ggatccatg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln ThrAla Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctgtct gaa ggt ggt aaa ttg aac gac gca att cgg 96 Ile Thr Ala Pro Leu SerGlu Gly Gly Lys Leu Asn Asp Ala Ile Arg 15 20 25 30 ggt ttg gtg tca cacatc tta atc cca cag cat acc ttg cga agt ctg 144 Gly Leu Val Ser His IleLeu Ile Pro Gln His Thr Leu Arg Ser Leu 35 40 45 act tcc cgt gct cgt tctgac aac ggt ggt tcg agt gga gca caa ata 192 Thr Ser Arg Ala Arg Ser AspAsn Gly Gly Ser Ser Gly Ala Gln Ile 50 55 60 tgc atc tgg aag gta tgt ccacca tcc cca tgg aga cga cca caa gga 240 Cys Ile Trp Lys Val Cys Pro ProSer Pro Trp Arg Arg Pro Gln Gly 65 70 75 aaa aga tgaatgacgt cagacaaccgccacaactgt agtacgacat cgttgatacg 296 Lys Arg 80 acttcagcaa atattttaacatcactgtgg ttgtgaagaa atcagttgct ttaaaagatt 356 ggatttttcc ttgtttaagagttgtactga tatcagctct gcactatgaa ataaagctga 416 tgtgacaaac aataaaaaagaaaaaaaaaa aagtactctg cgttgttact cgag 470 23 80 PRT Conus consors 23 MetGln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ala Ile Arg Gly Leu 20 25 30Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu Thr Ser 35 40 45Arg Ala Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 7580 24 28 PRT Conus consors PEPTIDE (1)..(28) Xaa at residues 16 and 24may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21, 23and 27 may be Pro or hydroxy-Pro 24 Ala Arg Ser Asp Asn Gly Gly Ser SerGly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa XaaArg Arg Xaa Gln 20 25 25 469 DNA Conus consors CDS (7)..(228) 25 ggatccatg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln ThrAla Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctgtct gaa ggt ggt aaa ttg aac gac gta att cgg 96 Ile Thr Ala Pro Leu SerGlu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca cacttc tta acc cca cag cat atc ttg caa agt ctg 144 Gly Leu Val Pro His PheLeu Thr Pro Gln His Ile Leu Gln Ser Leu 35 40 45 act tcc cgt aat ggt tctggc agc agt aat cag aaa gaa gca caa cta 192 Thr Ser Arg Asn Gly Ser GlySer Ser Asn Gln Lys Glu Ala Gln Leu 50 55 60 tgc atc tgg aag gta tgt ccacca tcc cca tgg aga tgaccacaag 238 Cys Ile Trp Lys Val Cys Pro Pro SerPro Trp Arg 65 70 gaaaaagatg aacggcgtca gacaaccgcc acaactgtag tgggacatcgttgatacgac 298 ttcagcaaat attttaacat cactgtggtt gtgaagaaat cagttgctttaaaagattgg 358 atttttcctt gtttaagaat tgtactgata tcagctctgc actatgaaataaagctgatg 418 tgacaaccca aaaaaaaaaa aaaaaaaaag tactctgcgt tgttactcga g469 26 74 PRT Conus consors 26 Met Gln Thr Ala Tyr Trp Val Met Val MetMet Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys LeuAsn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Phe Leu Thr Pro Gln HisIle Leu Gln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn GlnLys Glu Ala Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro TrpArg 65 70 27 25 PRT Conus consors PEPTIDE (1)..(25) Xaa at residue 10may be Glu or Gla; Xaa at residues 16 and 24 may be Trp (D or L) orbromo-Trp (D or L); Xaa at residues 20, 21 and 23 may be Pro orhydroxy-Pro 27 Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu CysIle Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Arg 20 25 28 472 DNAConus tulipa CDS (7)..(231) misc_feature (1)..(472) n may be any base 28ggatcc atg cag acg gcc tac tgg gtg atg ctg atg atg atg gtg tgg 48 MetGln Thr Ala Tyr Trp Val Met Leu Met Met Met Val Trp 1 5 10 att aca gcccct ctg tct gaa ggt ggt aaa ctg aac gac gta att cgg 96 Ile Thr Ala ProLeu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtgcca cac gtc tta acc cca cag cat atc ttg caa agt ctg 144 Gly Leu Val ProHis Val Leu Thr Pro Gln His Ile Leu Gln Ser Leu 35 40 45 gtt tcc cgt cgtcat ttt aac agc gtt gtt ccg acg gta tac ata tgc 192 Val Ser Arg Arg HisPhe Asn Ser Val Val Pro Thr Val Tyr Ile Cys 50 55 60 atg tgg aag gta tgtcca cca tcg cca tag aga cga cca taaggaaaaa 241 Met Trp Lys Val Cys ProPro Ser Pro Arg Arg Pro 65 70 gatgaatgac gtcagacaac cgccacaactgtagtacgac atcgttaata cgacttcagc 301 aaatatttta acatcactgt ggttgtgaagaaatcagttg ctttaaaaga ttggattttt 361 ccttgtttca gagttgtact gatatcagctctgcactatc aaataaagct gaagtgacaa 421 accnnaaaaa aaaaaaaaaa aaaaaaaaagtactctgcgt tgttactcga g 472 29 71 PRT Conus tulipa misc_feature(1)..(472) n may be any base 29 Met Gln Thr Ala Tyr Trp Val Met Leu MetMet Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys LeuAsn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Val Leu Thr Pro Gln HisIle Leu Gln Ser Leu Val Ser 35 40 45 Arg Arg His Phe Asn Ser Val Val ProThr Val Tyr Ile Cys Met Trp 50 55 60 Lys Val Cys Pro Pro Ser Pro 65 7030 21 PRT Conus tulipa PEPTIDE (1)..(21) Xaa at residues 7, 18, 19 and21 may be Pro or hydroxy-Pro; Xaa aT residue 10 may be Tyr, 125I-Tyr,mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa atresidue 14 may be Trp or bromo-Trp 30 His Phe Asn Ser Val Val Xaa ThrVal Xaa Ile Cys Met Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa 20 31 451DNA Conus tulipa CDS (1)..(279) 31 atg cag acg gcc tac tgg gtg atg ctgttg atg atg gtg ggc att aca 48 Met Gln Thr Ala Tyr Trp Val Met Leu LeuMet Met Val Gly Ile Thr 1 5 10 15 gcc cct ctg cct gaa ggt ggt aaa ccgaac agc gta att cgg ggt ttg 96 Ala Pro Leu Pro Glu Gly Gly Lys Pro AsnSer Val Ile Arg Gly Leu 20 25 30 gtg cca aac gac tta act cca cag cat accttg cga agt ctg att tcc 144 Val Pro Asn Asp Leu Thr Pro Gln His Thr LeuArg Ser Leu Ile Ser 35 40 45 cgt cgt caa act gac gtt ctt ctg gag gct accctt ttg aca aca cca 192 Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr LeuLeu Thr Thr Pro 50 55 60 gcc ccc gag cag aga ttg ttc tgc ttc tgg aag tcatgt tgg cca agg 240 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser CysTrp Pro Arg 65 70 75 80 ccc tac cct tgg aga cga cgt gat ctt aat gga aaacga tgaatgacgt 289 Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly Lys Arg85 90 cagacaaccg ccacaactgt agtacgacat cattaatacg acttcagcaa atattttaac349 attactgtgg ttgtgaagaa atcacttgct ttaaaagatt ggttttttcc ttgtttcaga409 gttgtactga tatcagctct gccctatgaa ataaagctga tg 451 32 93 PRT Conustulipa 32 Met Gln Thr Ala Tyr Trp Val Met Leu Leu Met Met Val Gly IleThr 1 5 10 15 Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser Val Ile ArgGly Leu 20 25 30 Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu Arg Ser LeuIle Ser 35 40 45 Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr Leu Leu ThrThr Pro 50 55 60 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys TrpPro Arg 65 70 75 80 Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly Lys Arg85 90 33 40 PRT Conus tulipa PEPTIDE (1)..(40) Xaa at residue 1 is Glnor pyro-Glu; Xaa at residue 7 and 17 may be Glu or Gla; Xaa at residue14, 16, 29, 31 and 33 may be Pro or hydroxy-Pro; Xaa at residues 24, 28and 34 may be Trp (D or L) or bromo-Trp (D or L) 33 Xaa Thr Asp Val LeuLeu Xaa Ala Thr Leu Leu Thr Thr Xaa Ala Xaa 1 5 10 15 Xaa Gln Arg LeuPhe Cys Phe Xaa Lys Ser Cys Xaa Xaa Arg Xaa Xaa 20 25 30 Xaa Xaa Arg ArgArg Asp Leu Asn 35 40 34 414 DNA Conus sulcatus CDS (1)..(285) 34 atgcag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met GlnThr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcccct ctg tct gaa ggt ggt aaa ccg aac gac gta att cgg ggt ttg 96 Ala ProLeu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg ccagac gac tta acc cca cag cgt gtc ttg cga agt ctg att tcc 144 Val Pro AspAsp Leu Thr Pro Gln Arg Val Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt caatct ggc tgc aga gtc ccg ttt gaa ttg aaa tgc atc tgg 192 Arg Arg Gln SerGly Cys Arg Val Pro Phe Glu Leu Lys Cys Ile Trp 50 55 60 aag ttc tgt acaata tac cca tcg aga cca ttt gct tct ctg gaa gaa 240 Lys Phe Cys Thr IleTyr Pro Ser Arg Pro Phe Ala Ser Leu Glu Glu 65 70 75 80 aaa gac gaa tgtcag aca gtc acc ata act gta aca tgg gat ttt 285 Lys Asp Glu Cys Gln ThrVal Thr Ile Thr Val Thr Trp Asp Phe 85 90 95 taatacgtct ccagcaagtattttaacatc actgtggttg tgaagaaatc agttgcttta 345 aaagattgga tttttccttgtttaagagtt gtactgatat cagctctgcc ctgtgaaata 405 aagctgatg 414 35 95 PRTConus sulcatus 35 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Pro Asn Asp ValIle Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Arg Val Leu ArgSer Leu Ile Ser 35 40 45 Arg Arg Gln Ser Gly Cys Arg Val Pro Phe Glu LeuLys Cys Ile Trp 50 55 60 Lys Phe Cys Thr Ile Tyr Pro Ser Arg Pro Phe AlaSer Leu Glu Glu 65 70 75 80 Lys Asp Glu Cys Gln Thr Val Thr Ile Thr ValThr Trp Asp Phe 85 90 95 36 45 PRT Conus sulcatus PEPTIDE (1)..(45) Xaaat residue 1 is Gln or pyro-Glu; Xaa at residues 7, 21 and 24 may be Proor hydroxy-Pro; Xaa at residues 9, 29, 30 and 33 may be Glu or Gla; Xaaat residues 14 and 43 may be Trp (D or L) or bromo-Trp (D or L) 36 XaaSer Gly Cys Arg Val Xaa Phe Xaa Leu Lys Cys Ile Xaa Lys Phe 1 5 10 15Cys Thr Ile Xaa Xaa Ser Arg Ser Phe Ala Ser Leu Xaa Xaa Lys Asp 20 25 30Xaa Cys Gln Thr Val Thr Ile Thr Val Thr Xaa Asp Phe 35 40 45 37 413 DNAConus sulcatus CDS (1)..(234) 37 atg cag acg gcc tac tgg gtg atg gtg atgatg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met MetMet Val Trp Ile Thr 1 5 10 15 gcc tct ctg tct gaa ggt ggt aaa ccg aacgac gtc att cgg ggt ttt 96 Ala Ser Leu Ser Glu Gly Gly Lys Pro Asn AspVal Ile Arg Gly Phe 20 25 30 gtg cca gac gac tta acc cca cag ctt atc ttgcga agt ctg att tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu ArgSer Leu Ile Ser 35 40 45 cgt cgt cgt tct gac aag gat gtt ggg aag aga atggaa tgt tac tgg 192 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys Arg Met GluCys Tyr Trp 50 55 60 aag gca tgt aga ccc acg cta tcg aga cga cat gat cttggg 234 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu Gly 65 70 75taaaagatga atgacgtcag acaacagcca caactatagt atgacatcgt taatacgact 294tcagcaaata ttttaacatc actgtggttg tgaagaaatc agttgcttta aaagattgga 354tttttccgtg tttaagagtt gtactgatat cagctctgcc ctgtgaaata aagctgatg 413 3878 PRT Conus sulcatus 38 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetVal Trp Ile Thr 1 5 10 15 Ala Ser Leu Ser Glu Gly Gly Lys Pro Asn AspVal Ile Arg Gly Phe 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile LeuArg Ser Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys ArgMet Glu Cys Tyr Trp 50 55 60 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg HisAsp Leu Gly 65 70 75 39 27 PRT Conus sulcatus PEPTIDE (1)..(27) Xaa atresidue 11 may be Glu or Gla; Xaa at residue 13 may be Pro orhydroxy-Pro; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D orL); Xaa at residue 19 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr,O-sulpho-Tyr or O-phospho-Tyr 39 Arg Ser Asp Lys Asp Val Gly Lys Arg MetXaa Cys Xaa Xaa Lys Ala 1 5 10 15 Cys Arg Xaa Thr Leu Ser Arg Arg HisAsp Leu 20 25 40 451 DNA Conus magus CDS (1)..(279) 40 atg cag acg gcctac tgg gtg atg ctg atg atg atg gtg tgc atc aca 48 Met Gln Thr Ala TyrTrp Val Met Leu Met Met Met Val Cys Ile Thr 1 5 10 15 gcc cct ctg cctgaa ggt ggt aaa ccg aac agc gga att cgg ggt ttg 96 Ala Pro Leu Pro GluGly Gly Lys Pro Asn Ser Gly Ile Arg Gly Leu 20 25 30 gtg cca aac gac ttaact cca cag cat acc ttg cga agt ctg att tcc 144 Val Pro Asn Asp Leu ThrPro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt caa act gac gttctt ctg gat gct acc ctt ttg aca aca cca 192 Arg Arg Gln Thr Asp Val LeuLeu Asp Ala Thr Leu Leu Thr Thr Pro 50 55 60 gcc ccc gag cag aga ttg ttctgc ttc tgg aag tca tgt tgg cca agg 240 Ala Pro Glu Gln Arg Leu Phe CysPhe Trp Lys Ser Cys Trp Pro Arg 65 70 75 80 ccc tac cct tgg aga cga cgtaat ctt aat gga aaa cga tgaatgacgt 289 Pro Tyr Pro Trp Arg Arg Arg AsnLeu Asn Gly Lys Arg 85 90 cagacaaccg ccacaactgt agtacgacat cgttaatacgacttcagcaa atattttaac 349 ataactgtgg ttgtgaagaa atcggttgct ttaaaagattggatttttcc ttgtttcaga 409 gttgtactga tatgagctct gccctgtgaa ataaagctga tg451 41 93 PRT Conus magus 41 Met Gln Thr Ala Tyr Trp Val Met Leu Met MetMet Val Cys Ile Thr 1 5 10 15 Ala Pro Leu Pro Glu Gly Gly Lys Pro AsnSer Gly Ile Arg Gly Leu 20 25 30 Val Pro Asn Asp Leu Thr Pro Gln His ThrLeu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Gln Thr Asp Val Leu Leu Asp AlaThr Leu Leu Thr Thr Pro 50 55 60 Ala Pro Glu Gln Arg Leu Phe Cys Phe TrpLys Ser Cys Trp Pro Arg 65 70 75 80 Pro Tyr Pro Trp Arg Arg Arg Asn LeuAsn Gly Lys Arg 85 90 42 40 PRT Conus magus PEPTIDE (1)..(40) Xaa atresidue 1 is Gln or pyro-Glu; Xaa at residues 14, 16, 29, 31 and 33 maybe Pro or hydroxy-Pro; Xaa at residue 17 may be Glu or Gla; Xaa atresidues 24, 28 and 34 may be Trp (D or L) or bromo-Trp (D or L) 42 XaaThr Asp Val Leu Leu Asp Ala Thr Leu Leu Thr Thr Xaa Ala Xaa 1 5 10 15Xaa Gln Arg Leu Phe Cys Phe Xaa Lys Ser Cys Xaa Xaa Arg Xaa Xaa 20 25 30Xaa Xaa Arg Arg Arg Asn Leu Asn 35 40 43 423 DNA Conus emaciatus CDS(1)..(249) 43 atg cag acg gcc tac tgg gtg atg gcg atg atg atg gtg tggatt aca 48 Met Gln Thr Ala Tyr Trp Val Met Ala Met Met Met Val Trp IleThr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cggggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg GlyLeu 20 25 30 gtg cca gat gac tta acc cca cag ctt gtt ttg caa agt ctg gattcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser35 40 45 cgt cgt cat act cac ggc att cgt ccg aag gga gac ggc ata tgt atc192 Arg Arg His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 5055 60 tgg aag gta tgt cca cca gac cca tgg aga cga cat cgt ctt aag aaa240 Trp Lys Val Cys Pro Pro Asp Pro Trp Arg Arg His Arg Leu Lys Lys 6570 75 80 aga aac aat tgacgtcaga caaccgccac aacttgagta cgacatcgtt 289 ArgAsn Asn aatacgactt cagcaaatat gaaattttca gcatcactgt ggttgtcaagaaatcagttg 349 ctttaaaaga ttggatttgt ccttgtttaa gagttgtact gatgtcagctctgccctgtg 409 aaataaagct gatg 423 44 83 PRT Conus emaciatus 44 Met GlnThr Ala Tyr Trp Val Met Ala Met Met Met Val Trp Ile Thr 1 5 10 15 AlaPro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 ValPro Asp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 ArgArg His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 TrpLys Val Cys Pro Pro Asp Pro Trp Arg Arg His Arg Leu Lys Lys 65 70 75 80Arg Asn Asn 45 33 PRT Conus emaciatus PEPTIDE (1)..(33) Xaa at residues7, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15 and 23may be Trp (D or L) or bromo-Trp (D or L) 45 His Thr His Gly Ile Arg XaaLys Gly Asp Gly Ile Cys Ile Xaa Lys 1 5 10 15 Val Cys Xaa Xaa Asp XaaXaa Arg Arg His Arg Leu Lys Lys Arg Asn 20 25 30 Asn 46 412 DNA Conuscircumcisus CDS (1)..(240) 46 atg cag acg gcc tac tgg gtg atg gtg atgatg gtg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met MetVal Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa tcg aacgac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Ser Asn AspVal Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttgcaa agt ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu GlnSer Leu Thr Ser 35 40 45 cgt ctt cgt tct gac agc agt ggt cag aaa gga gcacaa ata tgc atc 192 Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala GlnIle Cys Ile 50 55 60 tgg aag gta tgt cca cta tcc cca tgg aga cga cca caagga aaa aga 240 Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln GlyLys Arg 65 70 75 80 tgaatgacgt cagacaaccg ctacaactgt agtacgacatcgttgatacg acttcagcaa 300 atattttaac atcactgtgg ttgtgaagaa atcagttgctttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gccctgtgaaataaagctga tg 412 47 80 PRT Conus circumcisus 47 Met Gln Thr Ala Tyr TrpVal Met Val Met Met Val Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser GluGly Gly Lys Ser Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile LeuThr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu Arg Ser AspSer Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys ProLeu Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 75 80 48 28 PRT Conuscircumcisus PEPTIDE (1)..(28) Xaa at residues 16 and 24 may be Trp (D orL) or bromo-Trp (D or L); Xaa at residues 20, 23 and 27 may be Pro orhydroxy-Pro 48 Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile CysIle Xaa 1 5 10 15 Lys Val Cys Xaa Leu Ser Xaa Xaa Arg Arg Xaa Gln 20 2549 410 DNA Conus betulinus CDS (1)..(207) 49 atg cag acg gcc tac tgg gtgatg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val MetVal Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tcc gaa ggt ggtaaa ctg aac gat gta att cgg gct ttg 96 Ala Pro Leu Ser Glu Gly Gly LysLeu Asn Asp Val Ile Arg Ala Leu 20 25 30 gcg cca gac gac gta acc cca cagttt atc ttg cga agt ctg att tcc 144 Ala Pro Asp Asp Val Thr Pro Gln PheIle Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt cgt tct gac agc gat gtt cgggag gta ccc gta tgt tcc tgg 192 Arg Arg Arg Ser Asp Ser Asp Val Arg GluVal Pro Val Cys Ser Trp 50 55 60 aag ata tgt cca cca tagccatagagacgacatga tcttaaggaa aaagagaaat 247 Lys Ile Cys Pro Pro 65 gacgtcagacaaccgccaca actgtagtac ggcatcgtta atacgacttc agcaaatgtt 307 ttaacatcactgtggttgtg aagaaatcag ctgctttaaa agattggatt tttccttaag 367 agttgcactgatgtcagttc tgccctgtga aataaagctg atg 410 50 69 PRT Conus betulinus 50Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 1015 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Ala Leu 20 2530 Ala Pro Asp Asp Val Thr Pro Gln Phe Ile Leu Arg Ser Leu Ile Ser 35 4045 Arg Arg Arg Ser Asp Ser Asp Val Arg Glu Val Pro Val Cys Ser Trp 50 5560 Lys Ile Cys Pro Pro 65 51 19 PRT Conus betulinus PEPTIDE (1)..(19)Xaa at residue 8 may be Glu or Gla; Xaa at residues 10, 18 and 19 may bePro or hydroxy-Pro; Xaa at residue 14 may be Trp (D or L) or bromo-Trp(D or L) 51 Arg Ser Asp Ser Asp Val Arg Xaa Val Xaa Val Cys Ser Xaa LysIle 1 5 10 15 Cys Xaa Xaa 52 423 DNA Conus aurisiacus CDS (1)..(249) 52atg cag acg gcc tac tgg gtg atg gcg atg atg atg gtg tgg att aca 48 MetGln Thr Ala Tyr Trp Val Met Ala Met Met Met Val Trp Ile Thr 1 5 10 15gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 AlaPro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtgcca gat gac tta acc cca cag ctt gtt ttg caa agt ctg gat tcc 144 Val ProAsp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 cgt cgtcat act cac ggc att cgt ccg aag gga gac ggc ata tgt atc 192 Arg Arg HisThr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 tgg aag gtatgt cca cca gac cca tgg aga cga cat cat ctt aag aaa 240 Trp Lys Val CysPro Pro Asp Pro Trp Arg Arg His His Leu Lys Lys 65 70 75 80 aga aac aattgacgtcaga caaccgccac aacttgagta cgacatcgtt 289 Arg Asn Asn aatacgacttcagcaaatat gaaattttca gcatcactgt ggttgtcaag aaatcagttg 349 ctttaaaagattggatttgt ccttgtttaa gagttgtact gatgtcagct ctgccctatg 409 aaataaagctgatg 423 53 83 PRT Conus aurisiacus 53 Met Gln Thr Ala Tyr Trp Val MetAla Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly GlyLys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr ProGln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Thr His Gly IleArg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro AspPro Trp Arg Arg His His Leu Lys Lys 65 70 75 80 Arg Asn Asn 54 33 PRTConus aurisiacus PEPTIDE (1)..(33) Xaa at residues 7, 19, 20 and 22 maybe Pro or hydroxy-Pro; Xaa at residues 1 and 24 may be Trp (D or L) orbromo-Trp (D or L) 54 His Thr His Gly Ile Arg Xaa Lys Gly Asp Gly IleCys Ile Xaa Lys 1 5 10 15 Val Cys Xaa Xaa Asp Xaa Xaa Arg Arg His HisLeu Lys Lys Arg Asn 20 25 30 Asn 55 439 DNA Conus aurisiacus CDS(1)..(249) 55 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tggatt aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp IleThr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att tggggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Trp GlyLeu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agc ctg acttcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser35 40 45 cgt ctt cat tct gac agc agt gat cag aaa gga ggc atg aac gca tgg192 Arg Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Trp 5055 60 aca gga gca gga gca caa ata tgc atc tgg aag gta tgt cca cca ccc240 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Pro 6570 75 80 cca tgg aga tgaacacaag gaaaaagatg aatgacgtca gacaaccgcc 289 ProTrp Arg acaactgtag tacgacatcg ttgatacgac ttcagcaaat attttaacatcactgtggtt 349 gtgaagaaat cagttgcttt aaaagattgg atttttcctt gtttaagagttgtactgata 409 tcagctctgc cctgtgaagt aaagctgatg 439 56 83 PRT Conusaurisiacus 56 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val TrpIle Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val IleTrp Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln SerLeu Thr Ser 35 40 45 Arg Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly MetAsn Ala Trp 50 55 60 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val CysPro Pro Pro 65 70 75 80 Pro Trp Arg 57 34 PRT Conus aurisiacus PEPTIDE(1)..(34) Xaa at residues 15, 25 and 33 may be Trp (D or L) or bromo-Trp(D or L); Xaa at residues 29, 30, 31 and 32 may be Pro or hydroxy-Pro 57Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Xaa Thr 1 5 1015 Gly Ala Gly Ala Gln Ile Cys Ile Xaa Lys Val Cys Xaa Xaa Xaa Xaa 20 2530 Xaa Arg 58 412 DNA Conus aurisiacus CDS (1)..(222) 58 atg cag acg gcctac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tctgaa ggt ggt aaa ttg aac gac gta att tgg ggt ttg 96 Ala Pro Leu Ser GluGly Gly Lys Leu Asn Asp Val Ile Trp Gly Leu 20 25 30 gtg cca cac atc ttaacc cca cag cat atc ttg caa agc ctg act tcc 144 Val Pro His Ile Leu ThrPro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgt ctt cat tct gac agcagt gat cag aaa gga gca caa ata tgc atc 192 Arg Leu His Ser Asp Ser SerAsp Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca ccccca tgg aga tgaacacaag gaaaaagatg 242 Trp Lys Val Cys Pro Pro Pro ProTrp Arg 65 70 aatgacgtca gacaaccgcc acaactgtag tacgacatcg ttgatacgacttcagcaaat 302 attttaacat cactgtggtt gtgaagaaat cagttgcttt aaaagattggatttttcctt 362 gtttaggagt tgtattgata tcagctctgc cctgtgaaat aaagctgatg412 59 74 PRT Conus aurisiacus 59 Met Gln Thr Ala Tyr Trp Val Met ValMet Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly LysLeu Asn Asp Val Ile Trp Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro GlnHis Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu His Ser Asp Ser Ser AspGln Lys Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Pro ProTrp Arg 65 70 60 25 PRT Conus aurisiacus PEPTIDE (1)..(25) Xaa atresidues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa atresidues 20, 21, 22 and 23 may be Pro or hydroxy-Pro 60 Leu His Ser AspSer Ser Asp Gln Lys Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val CysXaa Xaa Xaa Xaa Xaa Arg 20 25 61 439 DNA Conus aurisiacus CDS (1)..(267)61 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 1015 gcc cct ctg ttt gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96Ala Pro Leu Phe Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30gtg cca cac atc tta acc cca cag cat atc ttg caa agc ctg act tcc 144 ValPro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgtctt cgt tct gac agc agt gat cag aaa gga ggc atg aac gca tcg 192 Arg LeuArg Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Ser 50 55 60 aca ggagca gga gca caa ata tgc atc tgg aag gta tgt cca cca tcc 240 Thr Gly AlaGly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser 65 70 75 80 cca tggaga cga aca caa gga aaa aga tgaatgacgt cagacaaccg 287 Pro Trp Arg ArgThr Gln Gly Lys Arg 85 ccacaactgt agtacgacat cgttgatacg acttcagcaaatattttaac atcactgtgg 347 ttgtgaagaa atcagttgct ttaaaagatt ggatttttccttgtttaaga gttgtactga 407 tatcagctct gcactgtgaa ataaagctga tg 439 62 89PRT Conus aurisiacus 62 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetVal Trp Ile Thr 1 5 10 15 Ala Pro Leu Phe Glu Gly Gly Lys Leu Asn AspVal Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile LeuGln Ser Leu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Ser Ser Asp Gln Lys GlyGly Met Asn Ala Ser 50 55 60 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp LysVal Cys Pro Pro Ser 65 70 75 80 Pro Trp Arg Arg Thr Gln Gly Lys Arg 8563 37 PRT Conus aurisiacus PEPTIDE (1)..(37) Xaa at residues 25 and 33may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 29, 30 and 32may be Pro or hydroxy-Pro 63 Leu Arg Ser Asp Ser Ser Asp Gln Lys Gly GlyMet Asn Ala Ser Thr 1 5 10 15 Gly Ala Gly Ala Gln Ile Cys Ile Xaa LysVal Cys Xaa Xaa Ser Xaa 20 25 30 Xaa Arg Arg Thr Gln 35 64 412 DNA Conusachatinus CDS (1)..(240) 64 atg cag acg gcc tac tgg gtg atg gtg atg atgatg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetVal Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gacgta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp ValIle Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caaagt ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln SerLeu Thr Ser 35 40 45 cgt ctt cgt tct gac aac ggt ggt tcg agt gga gca caaata tgc atc 192 Arg Leu Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln IleCys Ile 50 55 60 tgg aag gtg tgt cca cca tcc cca tgg aga cga cca caa ggaaaa aga 240 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln Gly LysArg 65 70 75 80 tgaacggcgt cagacaaccg ccacaactgt agtgggacat cgttgatacgacttcagcaa 300 atattttaac atcactgtgg ttgtgaagaa atcagttgct ttaaaagattggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gccctatgaa ataaagctga tg412 65 80 PRT Conus achatinus 65 Met Gln Thr Ala Tyr Trp Val Met Val MetMet Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys LeuAsn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln HisIle Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Asn Gly Gly SerSer Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro TrpArg Arg Pro Gln Gly Lys Arg 65 70 75 80 66 28 PRT Conus achatinusPEPTIDE (1)..(28) Xaa at residues 16 and 24 may be Trp (D or L) orbromo-Trp (D or L); Xaa at residues 20, 21, 23 and 27 may be Pro orhydroxy-Pro 66 Leu Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile CysIle Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Arg Arg Xaa Gln 20 2567 399 DNA Conus purpurascens CDS (1)..(213) 67 atg cag acg gcc tac tgggtg atg gtg atg acg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp ValMet Val Met Thr Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggtgga aaa ctg aac gat gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly GlyLys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gac gac tta gcc ctacag ctt atc ttg caa agt ccg gtt ttc 144 Val Pro Asp Asp Leu Ala Leu GlnLeu Ile Leu Gln Ser Pro Val Phe 35 40 45 cgt cgt caa tct gaa gag gaa aaaata tgc ctc tgg aag ata tgt cca 192 Arg Arg Gln Ser Glu Glu Glu Lys IleCys Leu Trp Lys Ile Cys Pro 50 55 60 cca ccc cca tgg aga cga tcataaggaaaaa aaaatgaatg acgtcagaca 243 Pro Pro Pro Trp Arg Arg Ser 65 70accaccacaa ctgtaatacg acatcgttaa tacgacttca gcaaacattt taacatcact 303gtggttgtga agaaatcagt tgctttagaa gcttggattt ttccttgttt aagagttgta 363ctgatatcag ctctgcccta tgaaataaag ctgatg 399 68 71 PRT Conus purpurascens68 Met Gln Thr Ala Tyr Trp Val Met Val Met Thr Met Val Trp Ile Thr 1 510 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 2025 30 Val Pro Asp Asp Leu Ala Leu Gln Leu Ile Leu Gln Ser Pro Val Phe 3540 45 Arg Arg Gln Ser Glu Glu Glu Lys Ile Cys Leu Trp Lys Ile Cys Pro 5055 60 Pro Pro Pro Trp Arg Arg Ser 65 70 69 21 PRT Conus purpurascensPEPTIDE (1)..(21) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues3,4 adn 5 may be Glu or Gla; Xaa at residues 10 and 18 may be Trp (D orL) or bromo-Trp (D or L); Xaa at residues 14, 15, 16 and 17 may be Proor hydroxy-Pro 69 Xaa Ser Xaa Xaa Xaa Lys Ile Cys Leu Xaa Lys Ile CysXaa Xaa Xaa 1 5 10 15 Xaa Xaa Arg Arg Ser 20 70 398 DNA Conuspurpurascens CDS (1)..(213) 70 atg cag acg gcc tac tgg gtg atg gtg atgatg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met MetMet Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gag ggt aga aaa ccg aacgat gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Arg Lys Pro Asn AspVal Ile Arg Gly Leu 20 25 30 gtg cca gat gac tta gcc cta cag ctt atc ttgcaa agt cag gtt tcc 144 Val Pro Asp Asp Leu Ala Leu Gln Leu Ile Leu GlnSer Gln Val Ser 35 40 45 cgt cgt gaa tct aat ggg gtg gaa ata tgc atg tggaag gta tgt cca 192 Arg Arg Glu Ser Asn Gly Val Glu Ile Cys Met Trp LysVal Cys Pro 50 55 60 cca tcc cca tgg aga cga tca taaggaaaaa aaatgaatgacgtcagacaa 243 Pro Ser Pro Trp Arg Arg Ser 65 70 ccaccacaac tgtaatacgacatcgttaat acgacttcag caaacatttt aacatcactg 303 tggttgtgaa gaaatcagttgctttaaaag attggatttt tccttgttta agagttgtac 363 tgatatcagc tctgccctatgaaataaagc tgatg 398 71 71 PRT Conus purpurascens 71 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu SerGlu Gly Arg Lys Pro Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp AspLeu Ala Leu Gln Leu Ile Leu Gln Ser Gln Val Ser 35 40 45 Arg Arg Glu SerAsn Gly Val Glu Ile Cys Met Trp Lys Val Cys Pro 50 55 60 Pro Ser Pro TrpArg Arg Ser 65 70 72 21 PRT Conus purpurascens PEPTIDE (1)..(21) Xaa atresidue 1 is Gln or pyro-Glu; Xaa at residue 6 may be Glu or Gla; Xaa atresidues 10 and 18 may be Trp (D or L) or bromo-Trp (D or L); Xaa atresidues 14, 15 and 17 may be Pro or hydroxy-Pro 72 Xaa Ser Asn Gly ValXaa Ile Cys Met Xaa Lys Val Cys Xaa Xaa Ser 1 5 10 15 Xaa Xaa Arg ArgSer 20 73 409 DNA Conus stercusmuscarum CDS (1)..(213) 73 atg cag acggcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr AlaTyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctgtct gaa ggt ggt aaa ttg acc gac gta att cgg ggt ttg 96 Ala Pro Leu SerGlu Gly Gly Lys Leu Thr Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atctta acc cca cag cat atc ttg caa agt atg act tcc 144 Val Pro His Ile LeuThr Pro Gln His Ile Leu Gln Ser Met Thr Ser 35 40 45 cgt ctt ggt att ggcagc agt gat caa aat gca caa ata tgc atc tgg 192 Arg Leu Gly Ile Gly SerSer Asp Gln Asn Ala Gln Ile Cys Ile Trp 50 55 60 aag gta tgt cca cca tcccca tagagacgac cataaggaaa aagatgaatg 243 Lys Val Cys Pro Pro Ser Pro 6570 acgtcagaca accgccacaa ctgtagtacg acatcgttga tacgacttca gcaaatattt 303taacatcact gtggttgtga agaaatcagt tgctttaaaa gattggattt ttccttgttt 363aagagttgta ctgatatcag ctctgccctg tgaaataaag ctgatg 409 74 71 PRT Conusstercusmuscarum 74 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Thr Asp ValIle Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu GlnSer Met Thr Ser 35 40 45 Arg Leu Gly Ile Gly Ser Ser Asp Gln Asn Ala GlnIle Cys Ile Trp 50 55 60 Lys Val Cys Pro Pro Ser Pro 65 70 75 22 PRTConus stercusmuscarum PEPTIDE (1)..(22) Xaa at residue 15 may be Trp orbromo-Trp; Xaa at residue 19, 20 and 22 may be Pro or hydroxy-Pro 75 LeuGly Ile Gly Ser Ser Asp Gln Asn Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15Val Cys Xaa Xaa Ser Xaa 20 76 433 DNA Conus baileyi CDS (1)..(216) 76atg cag acg gcc tac tgg gtg atg gtg atg ata atg gtg tgg att aca 48 MetGln Thr Ala Tyr Trp Val Met Val Met Ile Met Val Trp Ile Thr 1 5 10 15gtc cct ctg tct gaa ggt ggt aaa ttg aac gac ata att cgg ggt ttg 96 ValPro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ile Ile Arg Gly Leu 20 25 30 ttgcca gac aac ttc ccc cca cag ctt acc ttg cat cgt ctg gtt tcc 144 Leu ProAsp Asn Phe Pro Pro Gln Leu Thr Leu His Arg Leu Val Ser 35 40 45 cgt cgtcat tct gac agc att att ctg agg ggc tta tgt atc tgg aag 192 Arg Arg HisSer Asp Ser Ile Ile Leu Arg Gly Leu Cys Ile Trp Lys 50 55 60 gtg tgt gaacct ccg cca caa aga tgatctggtc caaagccaaa aaacgaatga 246 Val Cys Glu ProPro Pro Gln Arg 65 70 tgtcagacaa ccgccacagc tttagtacga catggttaatacgacttcag caaatatttc 306 aacatcactg tggttgtgaa gaaatcagtt actttaaaagattggaatga tgtcagctgt 366 gcactatcaa ataaagttga tgtgacaaaa aaaaaaaaaaaaaaagtact ctgcgttgtt 426 actcgag 433 77 72 PRT Conus baileyi 77 Met GlnThr Ala Tyr Trp Val Met Val Met Ile Met Val Trp Ile Thr 1 5 10 15 ValPro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ile Ile Arg Gly Leu 20 25 30 LeuPro Asp Asn Phe Pro Pro Gln Leu Thr Leu His Arg Leu Val Ser 35 40 45 ArgArg His Ser Asp Ser Ile Ile Leu Arg Gly Leu Cys Ile Trp Lys 50 55 60 ValCys Glu Pro Pro Pro Gln Arg 65 70 78 22 PRT Conus baileyi PEPTIDE(1)..(22) Xaa at residue 13 may be Trp (D or L) or bromo-Trp (D or L);Xaa at residue 17 may be Glu or Gla; Xaa at residues 18, 19 and 20 maybe Pro or hydroxy-Pro 78 His Ser Asp Ser Ile Ile Leu Arg Gly Leu Cys IleXaa Lys Val Cys 1 5 10 15 Xaa Xaa Xaa Xaa Gln Arg 20 79 413 DNA Conusbocki CDS (1)..(270) 79 atg cag acg gcc tac tgg gtg atg gtg atg atg atggtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 gcc cct ctg tct gaa agt gat aaa ctg aac gac gtaatt cgg ggt ttg 96 Ala Pro Leu Ser Glu Ser Asp Lys Leu Asn Asp Val IleArg Gly Leu 20 25 30 gtg cca gac aac tta acc cca cag ctt atc ttg cga agtctg att tcc 144 Val Pro Asp Asn Leu Thr Pro Gln Leu Ile Leu Arg Ser LeuIle Ser 35 40 45 cgt cgt cgt tct gac aag gat gat ccg gga gga caa gaa tgttac tgg 192 Arg Arg Arg Ser Asp Lys Asp Asp Pro Gly Gly Gln Glu Cys TyrTrp 50 55 60 aac gta tgt gca cca aac cag gga gac cac atg atc tta aga aaaaag 240 Asn Val Cys Ala Pro Asn Gln Gly Asp His Met Ile Leu Arg Lys Lys65 70 75 80 atg aat gac gac aga caa ccg cca caa ctg taatacgacatcgttaatac 290 Met Asn Asp Asp Arg Gln Pro Pro Gln Leu 85 90 gacttcagcaaatattttaa catcactgtg gttgtgaaga aatcagttgc tttaaaagat 350 tggatttttccgtgtttaag agctgtactg atatctgctc tgccctgtga aataaagctg 410 atg 413 80 90PRT Conus bocki 80 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Ser Asp Lys Leu Asn Asp ValIle Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Thr Pro Gln Leu Ile Leu ArgSer Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp Lys Asp Asp Pro Gly Gly GlnGlu Cys Tyr Trp 50 55 60 Asn Val Cys Ala Pro Asn Gln Gly Asp His Met IleLeu Arg Lys Lys 65 70 75 80 Met Asn Asp Asp Arg Gln Pro Pro Gln Leu 8590 81 40 PRT Conus bocki PEPTIDE (1)..(40) Xaa at residues 7, 19, 37, 38may be Pro or hydroxy-Pro; Xaa at residue 11 may be Glu or Gla; Xaa atresidue 14 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 13may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr orO-phospho-Tyr 81 Arg Ser Asp Lys Asp Asp Xaa Gly Gly Gln Xaa Cys Xaa XaaAsn Val 1 5 10 15 Cys Ala Xaa Asn Gln Gly Asp His Met Ile Leu Arg LysLys Met Asn 20 25 30 Asp Asp Arg Gln Xaa Xaa Gln Leu 35 40 82 496 DNAConus chaldaeus CDS (21)..(260) 82 gaattcgccc ttatggatcc atg cag acg gcctac tgg gtg atg atg ggg atg 53 Met Gln Thr Ala Tyr Trp Val Met Met GlyMet 1 5 10 atg atg gtg tgg att aca gcc cct ctg tct gga ggt ggt aaa ctgaac 101 Met Met Val Trp Ile Thr Ala Pro Leu Ser Gly Gly Gly Lys Leu Asn15 20 25 gac gta att cgg ggt ttg gtg cca gac gac tta acc cta cag cgt atg149 Asp Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met 3035 40 ttc gaa act ccg gtt tcc cat cgt ctt tct gag ggc aga aat tcg acg197 Phe Glu Thr Pro Val Ser His Arg Leu Ser Glu Gly Arg Asn Ser Thr 4550 55 gta cac ata tgt acg tgg aag gta tgt cca cct ccc cca tgg aga cga245 Val His Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro Trp Arg Arg 6065 70 75 cca cat gga caa aga tgaatgacgt cagacaacct ccacaactgt agtacgacat300 Pro His Gly Gln Arg 80 cgttaacacg acgtcagcta atcttttaac atcactgtggctgtgaagaa ctcggttgct 360 ttaaaagatt ggatttttcc ttgtttaaga gttgtgctgatatgaactct gcactacgaa 420 ataaagctga tgtgacaaac aaaaaaaaga aaaaaaaaagtactctgcgt tgttactcga 480 gcttaagggc gaattc 496 83 80 PRT Conuschaldaeus 83 Met Gln Thr Ala Tyr Trp Val Met Met Gly Met Met Met Val TrpIle 1 5 10 15 Thr Ala Pro Leu Ser Gly Gly Gly Lys Leu Asn Asp Val IleArg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Glu ThrPro Val 35 40 45 Ser His Arg Leu Ser Glu Gly Arg Asn Ser Thr Val His IleCys Thr 50 55 60 Trp Lys Val Cys Pro Pro Pro Pro Trp Arg Arg Pro His GlyGln Arg 65 70 75 80 84 29 PRT Conus chaldaeus PEPTIDE (1)..(29) Xaa atresidue 3 may be Glu or Gla; Xaa at residues 14 and 22 may be Trp (D orL) or bromo-Trp (D or L); Xaa at residues 18, 19, 20, 21 and 25 may bePro or hydroxy-Pro 84 Leu Ser Xaa Gly Arg Asn Ser Thr Val His Ile CysThr Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Xaa Xaa Xaa Arg Arg Xaa His GlyGln Arg 20 25 85 499 DNA Conus chaldaeus CDS (21)..(260) 85 gaattcgcccttatggatcc atg cag acg gcc tac tgg gtg atg atg ggg atg 53 Met Gln ThrAla Tyr Trp Val Met Met Gly Met 1 5 10 atg atg gtg tgg att aca gcc cctctg tct gga ggt ggt aaa ctg aac 101 Met Met Val Trp Ile Thr Ala Pro LeuSer Gly Gly Gly Lys Leu Asn 15 20 25 gac gta att cgg ggt ttg gtg cca gacgac tta acc cta cag cgt atg 149 Asp Val Ile Arg Gly Leu Val Pro Asp AspLeu Thr Leu Gln Arg Met 30 35 40 ttc gaa act ccg gtt tcc cat cgt ctt tctgag ggc aga aat tcg acg 197 Phe Glu Thr Pro Val Ser His Arg Leu Ser GluGly Arg Asn Ser Thr 45 50 55 gta cac ata tgt atg tgg aag gta tgt cca cctccc cca tgg aga cga 245 Val His Ile Cys Met Trp Lys Val Cys Pro Pro ProPro Trp Arg Arg 60 65 70 75 cca cat gga caa aga tgaatgacgt cagacaacctccacaactgt agtacgacat 300 Pro His Gly Gln Arg 80 cgttaacacg acgtcagctaatcttttaac atcactgtgg ttgtgaagaa atcggttgct 360 ttaaaagatt ggatttttccttgtttaaga gttgtgctga tatgaactct gcactacgaa 420 ataaagctga tgtgacaaacggaaaaaaaa aaaaaaaaaa aagtactctg cgttgttact 480 cgagcttaag ggcgaattc 49986 80 PRT Conus chaldaeus 86 Met Gln Thr Ala Tyr Trp Val Met Met Gly MetMet Met Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Gly Gly Gly Lys LeuAsn Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Leu Gln ArgMet Phe Glu Thr Pro Val 35 40 45 Ser His Arg Leu Ser Glu Gly Arg Asn SerThr Val His Ile Cys Met 50 55 60 Trp Lys Val Cys Pro Pro Pro Pro Trp ArgArg Pro His Gly Gln Arg 65 70 75 80 87 29 PRT Conus chaldaeus PEPTIDE(1)..(29) Xaa at residue 3 may be Glu or Gla; Xaa at residues 14 and 22may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19, 20,21 and 25 may be Pro or hydroxy-Pro 87 Leu Ser Xaa Gly Arg Asn Ser ThrVal His Ile Cys Met Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Xaa Xaa Xaa ArgArg Xaa His Gly Gln Arg 20 25 88 490 DNA Conus cinereus CDS (21)..(305)88 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 ttg gtg tgg att acagcc cct ctg cct gag ggt ggt aaa ccg aag cac 101 Leu Val Trp Ile Thr AlaPro Leu Pro Glu Gly Gly Lys Pro Lys His 15 20 25 gta att cgg ggt ttg gtacca gac gac tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val ProAsp Asp Leu Thr Pro Gln His Ile Leu 30 35 40 cga agt ttg att tcc cgt cgttca tct ggc tgc agt gtt tcg ttg ggc 197 Arg Ser Leu Ile Ser Arg Arg SerSer Gly Cys Ser Val Ser Leu Gly 45 50 55 ttc aaa tgc ttc tgg aag agc tgtaca gta atc cca gtg aga cca ttt 245 Phe Lys Cys Phe Trp Lys Ser Cys ThrVal Ile Pro Val Arg Pro Phe 60 65 70 75 gta tct ctg gaa gaa gaa aat gaatgc cag aaa gtc caa ata agt gca 293 Val Ser Leu Glu Glu Glu Asn Glu CysGln Lys Val Gln Ile Ser Ala 80 85 90 gta tgg ggt cct tgatacgacttcagcaagga tcactgtggt tgtgaagaaa 345 Val Trp Gly Pro 95 tcagttgctttaaaagattt gatttttcct tgtttaagag ttgtactgat atcagctctg 405 tactatgaaataaagctgat gtgacaaaca aaaaaaaaaa aaaaaaaagt actctgcgtt 465 gttactcgagcttaagggcg aattc 490 89 95 PRT Conus cinereus 89 Met Gln Thr Ala Tyr TrpVal Met Val Met Met Leu Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Pro GluGly Gly Lys Pro Lys His Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp LeuThr Pro Gln His Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Ser Ser GlyCys Ser Val Ser Leu Gly Phe Lys Cys Phe Trp 50 55 60 Lys Ser Cys Thr ValIle Pro Val Arg Pro Phe Val Ser Leu Glu Glu 65 70 75 80 Glu Asn Glu CysGln Lys Val Gln Ile Ser Ala Val Trp Gly Pro 85 90 95 90 45 PRT Conuscinereus PEPTIDE (1)..(45) Xaa at residues 14 and 43 may be Trp (D or L)or bromo-Trp (D or L); Xaa at residues 21, 24 and 45 may be Pro orhydroxy-Pro; Xaa at residues 29, 30, 31 adn 33 may be Glu or Gla 90 SerSer Gly Cys Ser Val Ser Leu Gly Phe Lys Cys Phe Xaa Lys Ser 1 5 10 15Cys Thr Val Ile Xaa Val Arg Xaa Phe Val Ser Leu Xaa Xaa Xaa Asn 20 25 30Xaa Cys Gln Lys Val Gln Ile Ser Ala Val Xaa Gly Xaa 35 40 45 91 497 DNAConus cinereus CDS (21)..(263) 91 gaattcgccc ttatggatcc atg cag acg gcctac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val MetMet 1 5 10 gtg gtg gtg tgg att aca gcc cct ctg cct gaa ggt ggt aaa ccggag 101 Val Val Val Trp Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Glu15 20 25 cac gta att cgg ggt ttg gtg cca gac gac tta acc cca cag ctt atc149 His Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile 3035 40 ttg cga agt ctg att tcc cgt cgt agt tct gac ggc aag gca aaa aga197 Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Arg 4550 55 aat tgt ttc tgg aag gca tgt gta cca gaa caa tgg aga caa cgt gat245 Asn Cys Phe Trp Lys Ala Cys Val Pro Glu Gln Trp Arg Gln Arg Asp 6065 70 75 ctt aag gaa aaa gat gaa tgatgtcaga caaccgccat cactgtagta 293Leu Lys Glu Lys Asp Glu 80 tgacatcgtt aatacgactt aagcaaatat tttaacatcactgtggatct gaagaaatca 353 gttgctttaa aagattggat ttttcctcgt ttaagagttgtactgatgtc agctctgcac 413 tgtgaaataa agctgatgtg acaaacgaaa aaaaaaaaaaaaaaaaagta ctctgcgttg 473 ttactcgagc ttaagggcga attc 497 92 81 PRT Conuscinereus 92 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Val Val Val TrpIle 1 5 10 15 Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Glu His Val IleArg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg SerLeu Ile 35 40 45 Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys PheTrp Lys 50 55 60 Ala Cys Val Pro Glu Gln Trp Arg Gln Arg Asp Leu Lys GluLys Asp 65 70 75 80 Glu 93 30 PRT Conus cinereus PEPTIDE (1)..(30) Xaaat residues 12 and 20 may be Trp (D or L) or bromo-Trp (D or L); Xaa atresidue 17 may be Pro or hydroxy-Pro; Xaa at residues 18, 27 and 30 maybe Glu or Gla 93 Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Xaa Lys AlaCys Val 1 5 10 15 Xaa Xaa Gln Xaa Arg Gln Arg Asp Leu Lys Xaa Lys AspXaa 20 25 30 94 496 DNA Conus cinereus CDS (21)..(263) 94 gaattcgcccttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln ThrAla Tyr Trp Val Met Val Met Met 1 5 10 atg gtg gtg tgg att aca gcc cctctg cct gaa ggt ggt aaa ccg aag 101 Met Val Val Trp Ile Thr Ala Pro LeuPro Glu Gly Gly Lys Pro Lys 15 20 25 cac gta att cgg ggt ttg gtg cca gacgac tta acc cca cag ctt atc 149 His Val Ile Arg Gly Leu Val Pro Asp AspLeu Thr Pro Gln Leu Ile 30 35 40 ttg cga agt ctg att tcc cgt cgt agt tctgac ggc aag gca aaa aga 197 Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser AspGly Lys Ala Lys Arg 45 50 55 aat tgt ttc tgg aag gca tgt gta cca gaa caatgg aga caa cgt gat 245 Asn Cys Phe Trp Lys Ala Cys Val Pro Glu Gln TrpArg Gln Arg Asp 60 65 70 75 cct aag gaa aaa gat gaa tgatgtcagacaaccgccat cactgtagta 293 Pro Lys Glu Lys Asp Glu 80 tgacatcgttaatacgactt aagcaaatat tttaacatca ctgtggatct gaagaaatca 353 gttgctttaaaagattggat ttttcctcgt ttaagagttg tactgatgtc agctctgcac 413 tgtgaaataaagctgacgtg acaagcaaaa aaaaaaaaaa aaaaaagtac tctgcgttgt 473 tactcgagcttaagggcgaa ttc 496 95 81 PRT Conus cinereus 95 Met Gln Thr Ala Tyr TrpVal Met Val Met Met Met Val Val Trp Ile 1 5 10 15 Thr Ala Pro Leu ProGlu Gly Gly Lys Pro Lys His Val Ile Arg Gly 20 25 30 Leu Val Pro Asp AspLeu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile 35 40 45 Ser Arg Arg Ser SerAsp Gly Lys Ala Lys Arg Asn Cys Phe Trp Lys 50 55 60 Ala Cys Val Pro GluGln Trp Arg Gln Arg Asp Pro Lys Glu Lys Asp 65 70 75 80 Glu 96 30 PRTConus cinereus PEPTIDE (1)..(30) Xaa at residues 12 and 20 may be Trp (Dor L) or bromo-Trp (D or L); Xaa at residues 17 and 25 may be Pro orhydroxy-Pro; Xaa at residues 18, 27 and 30 may be Glu or Gla 96 Ser SerAsp Gly Lys Ala Lys Arg Asn Cys Phe Xaa Lys Ala Cys Val 1 5 10 15 XaaXaa Gln Xaa Arg Gln Arg Asp Xaa Lys Xaa Lys Asp Xaa 20 25 30 97 493 DNAConus cinereus CDS (21)..(260) 97 gaattcgccc ttatggatcc atg cag acg gcctac tgg gtg atg gtg ata atg 53 Met Gln Thr Ala Tyr Trp Val Met Val IleMet 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ccg aagcac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys His15 20 25 gta att cgg ggt ttg gtg cca gtc gac tta acc cca cag ctt atc ttg149 Val Ile Arg Gly Leu Val Pro Val Asp Leu Thr Pro Gln Leu Ile Leu 3035 40 cga agt ctg att tcc cgt cgt agt tct gac ggc aag gca aaa aaa caa197 Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Lys Gln 4550 55 tgt gcc tgg aag aca tgt gta cca acc caa tgg aga cga cgt gat ctt245 Cys Ala Trp Lys Thr Cys Val Pro Thr Gln Trp Arg Arg Arg Asp Leu 6065 70 75 aag gaa aaa gat gaa tgatgtcaga caaccgccat cactgtagta tgacatcgtt300 Lys Glu Lys Asp Glu 80 aatacgactt aagcaaatat tttaacatca ctgtggttctgaagaaatca gttgctttaa 360 aagattggat ttttccttgt ttaagagttg tactgatatcagctctgcac tgtgaaataa 420 agctgatgtg acaaacaaaa aaaaaaaaaa aaaaaagtactctgcgttgt tactcgagct 480 taagggcgaa ttc 493 98 80 PRT Conus cinereus 98Met Gln Thr Ala Tyr Trp Val Met Val Ile Met Met Val Trp Ile Thr 1 5 1015 Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys His Val Ile Arg Gly Leu 20 2530 Val Pro Val Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 4045 Arg Arg Ser Ser Asp Gly Lys Ala Lys Lys Gln Cys Ala Trp Lys Thr 50 5560 Cys Val Pro Thr Gln Trp Arg Arg Arg Asp Leu Lys Glu Lys Asp Glu 65 7075 80 99 30 PRT Conus cinereus PEPTIDE (1)..(30) Xaa at residues 12 and20 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 17 may bePro or hydroxy-Pro; Xaa at residues 27 and 30 may be Glu or Gla 99 SerSer Asp Gly Lys Ala Lys Lys Gln Cys Ala Xaa Lys Thr Cys Val 1 5 10 15Xaa Thr Gln Xaa Arg Arg Arg Asp Leu Lys Xaa Lys Asp Xaa 20 25 30 100 496DNA Conus circumcisus CDS (21)..(263) 100 gaattcgccc ttatggatcc atg cagacg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val MetVal Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaattg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys LeuAsn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac atc tta acc cca cag catatc ttg 149 Val Ile Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His IleLeu 30 35 40 caa ggt ctg act tcc cgt ctt cgt tct gac agc agt ggt cag aaagga 197 Gln Gly Leu Thr Ser Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly45 50 55 gca caa ata tgc atc tgg aag gta tgt cca cta tcc cca tgg aga cga245 Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg 6065 70 75 cca caa gga aaa gat gaa tgacgtcaga caaccgctac aactgtagta 293Pro Gln Gly Lys Asp Glu 80 cgacatcgtt gatacgactt cagcaaatat tttaacatcactgtggttgt gaagaaatca 353 gctgctttaa aagattggat ttttccttgt ttaagagttgtactgatatc agctctgcac 413 tatgaaataa agctgatgtg acaaacaaaa aaaaaaaaaaaaaaaagtac tctgcgttgt 473 tactcgagct taagggcgaa ttc 496 101 81 PRT Conuscircumcisus 101 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val TrpIle Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val IleArg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln GlyLeu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala GlnIle Cys Ile 50 55 60 Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro GlnGly Lys Asp 65 70 75 80 Glu 102 32 PRT Conus circumcisus PEPTIDE(1)..(32) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (Dor L); Xaa at residues 20, 23 and 27 may be Pro or hydroxy-Pro; Xaa atresidue 32 may be Glu or Gla 102 Leu Arg Ser Asp Ser Ser Gly Gln Lys GlyAla Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Leu Ser Xaa Xaa ArgArg Xaa Gln Gly Lys Asp Xaa 20 25 30 103 496 DNA Conus consors CDS(21)..(242) 103 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atggtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atggtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met ValTrp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta attcgg ggt ttg gtg cca cac ttc tta acc cca cag cat atc ttg 149 Val Ile ArgGly Leu Val Pro His Phe Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctgact tcc cgt aat ggt tct ggc agc agt aat cag aaa gaa 197 Gln Ser Leu ThrSer Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu 45 50 55 gca caa cta tgcatc tgg aag gta tgt cca cca acc cca tgg aga 242 Ala Gln Leu Cys Ile TrpLys Val Cys Pro Pro Thr Pro Trp Arg 60 65 70 tgaccacaag gaaaaagatgaacggcgtca gacaaccgcc acaactgtag tgggacatcg 302 ttgatacgac ttcagcaaatattttaacat cactgtggtt gtgaagaaat cagttgtttt 362 aaaagattgg atttttccttgtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaagcaaaaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgagc 482 ttaagggcga attc 496 10474 PRT Conus consors 104 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetVal Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn AspVal Ile Arg Gly Leu 20 25 30 Val Pro His Phe Leu Thr Pro Gln His Ile LeuGln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys GluAla Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Thr Pro Trp Arg 6570 105 25 PRT Conus consors PEPTIDE (1)..(25) Xaa at residue 10 may beGlu or Gla ; Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp(D or L); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 105Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu Cys Ile Xaa 1 5 1015 Lys Val Cys Xaa Xaa Thr Xaa Xaa Arg 20 25 106 496 DNA Conus consorsCDS (21)..(242) 106 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtgatg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ctg aac ggc 101 MetVal Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Gly 15 20 25 gtaatt cgg ggt ttg gtg tca cac atc tta atc cca cag cat acc ttg 149 Val IleArg Gly Leu Val Ser His Ile Leu Ile Pro Gln His Thr Leu 30 35 40 cga agtctg act tcc cgt gat cgt tct gac aac ggt ggt tcg agt gga 197 Arg Ser LeuThr Ser Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly 45 50 55 gca caa atatgc atc tgg aag gta tgt cca cca tcc cca tgg aaa 242 Ala Gln Ile Cys IleTrp Lys Val Cys Pro Pro Ser Pro Trp Lys 60 65 70 tgaccacaag gaaaaagatgaacggcgtca gacaaccacc acaactgtag tgggacatcg 302 ttgatacgac ttcagcaaatattttaacat cactgtggtc gtgaagaaat cagttgcttt 362 aaaagattgg atttttccttgtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaaacaaaaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgagc 482 ttaagggcga attc 496 10774 PRT Conus consors 107 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetVal Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn GlyVal Ile Arg Gly Leu 20 25 30 Val Ser His Ile Leu Ile Pro Gln His Thr LeuArg Ser Leu Thr Ser 35 40 45 Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser GlyAla Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Lys 6570 108 25 PRT Conus consors PEPTIDE (1)..(25) Xaa at residues 16 and 24may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21 and 23may be Pro or hydroxy-Pro 108 Asp Arg Ser Asp Asn Gly Gly Ser Ser GlyAla Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Lys 2025 109 459 DNA Conus coronatus CDS (1)..(240) 109 atg cag acg gcc tactgg gtg atg atg atg atg atg atg gtg tgg att 48 Met Gln Thr Ala Tyr TrpVal Met Met Met Met Met Met Val Trp Ile 1 5 10 15 aca gcc cct ctg tctgaa ggt ggt aaa ctg aac gac gta att cgg ggt 96 Thr Ala Pro Leu Ser GluGly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 ttg gtg cca gac gac ttaacc cta cag cgt atg ttc aaa gct ctg gtt 144 Leu Val Pro Asp Asp Leu ThrLeu Gln Arg Met Phe Lys Ala Leu Val 35 40 45 tcc cat cgt ctt tct gac ggcaga gat tgg acg gga tac ata tgt atc 192 Ser His Arg Leu Ser Asp Gly ArgAsp Trp Thr Gly Tyr Ile Cys Ile 50 55 60 tgg aag gca tgt cca cgt ccc ccatgg atc cca cca aag gga aaa aga 240 Trp Lys Ala Cys Pro Arg Pro Pro TrpIle Pro Pro Lys Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaaccg ccacaactgtagtacgacat cgttaacaca acttcagcta 300 atattttaac atcactgtgg ttgtgaagaaatcggttgct ttaaaagatt gaatttttcg 360 tttaagagtt gtgctgatac gagctctgcactatgaaata aagctgatgt gacaaacaaa 420 aaaaaaaaaa aaaaaaagta ctctgcgttgttactcgag 459 110 80 PRT Conus coronatus 110 Met Gln Thr Ala Tyr Trp ValMet Met Met Met Met Met Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser GluGly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp LeuThr Leu Gln Arg Met Phe Lys Ala Leu Val 35 40 45 Ser His Arg Leu Ser AspGly Arg Asp Trp Thr Gly Tyr Ile Cys Ile 50 55 60 Trp Lys Ala Cys Pro ArgPro Pro Trp Ile Pro Pro Lys Gly Lys Arg 65 70 75 80 111 26 PRT Conuscoronatus PEPTIDE (1)..(26) Xaa at residues 7, 14 and 22 may be Trp orbromo-Trp; Xaa at residue 10 may be Tyr, 125I-Tyr, mono-iodo-Tyr,di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 18, 29, 21,24 and 25 may be Pro or hydroxy-Pro 111 Leu Ser Asp Gly Arg Asp Xaa ThrGly Xaa Ile Cys Ile Xaa Lys Ala 1 5 10 15 Cys Xaa Arg Xaa Xaa Xaa IleXaa Xaa Lys 20 25 112 495 DNA Conus ebraeus CDS (21)..(236) 112gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg atg 53 MetGln Thr Ala Tyr Trp Val Met Met Met Met 1 5 10 atg atg gtg tgg att acagcc cct ctg tct gaa ggc ggt aaa ctg aac 101 Met Met Val Trp Ile Thr AlaPro Leu Ser Glu Gly Gly Lys Leu Asn 15 20 25 gac gta att cgg ggt ttg gtgcca gac gac tta acc cta cag cgt atg 149 Asp Val Ile Arg Gly Leu Val ProAsp Asp Leu Thr Leu Gln Arg Met 30 35 40 ttc aaa agt ctg ttt tcc cat cgtctt tct ggc ggc aca tat tcg agg 197 Phe Lys Ser Leu Phe Ser His Arg LeuSer Gly Gly Thr Tyr Ser Arg 45 50 55 gta gac aca tgc atc tgg aag gta tgtcca caa tct cca tagggacgat 246 Val Asp Thr Cys Ile Trp Lys Val Cys ProGln Ser Pro 60 65 70 catatggaaa aagatgagtg acatcagaca actgccacaactgtagtacg acatcgttaa 306 cacgacttca gctaatattt taacatcact gtggttgtgaagaaatcggt tgctttaaaa 366 gattggattt ttccttgttt aagagttgtg ctgatatgagctctgcacta tgaaataaag 426 ctgatgtgac aaacaaaaaa aaaaaaaaaa aagtactctgcgttgttact cgagcttaag 486 ggcgaattc 495 113 72 PRT Conus ebraeus 113 MetGln Thr Ala Tyr Trp Val Met Met Met Met Met Met Val Trp Ile 1 5 10 15Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Lys Ser Leu Phe 35 40 45Ser His Arg Leu Ser Gly Gly Thr Tyr Ser Arg Val Asp Thr Cys Ile 50 55 60Trp Lys Val Cys Pro Gln Ser Pro 65 70 114 21 PRT Conus ebraeus PEPTIDE(1)..(21) Xaa at residue 6 may be Tyr, 125I-Tyr, mono-iodo-Tyr,di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residue 14 may be Trp(D or L) or bromo-Trp (D or L); Xaa at residues 18 and 21 may be Pro orhydroxy-Pro 114 Leu Ser Gly Gly Thr Xaa Ser Arg Val Asp Thr Cys Ile XaaLys Val 1 5 10 15 Cys Xaa Gln Ser Xaa 20 115 537 DNA Conus geographusCDS (21)..(299) 115 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtgatg ctg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met 1 5 10atg gtg tgc atc aca gcc cct ctg cct gaa ggt ggt aaa ccg aac agc 101 MetVal Cys Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser 15 20 25 ggaatt cgg ggt ttg gtg cca aac gac tta act cca cag cat acc ttg 149 Gly IleArg Gly Leu Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu 30 35 40 cga agtctg att tcc cgt cgt caa act gac gtt ctt ctg gag gct acc 197 Arg Ser LeuIle Ser Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr 45 50 55 ctt ttg acaaca cca gcc ccc gag cag aga ttg ttc tgc ttc tgg aag 245 Leu Leu Thr ThrPro Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys 60 65 70 75 tca tgt acgtgg agg ccc tac cct tgg aga cga cgt gat ctt aat gga 293 Ser Cys Thr TrpArg Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly 80 85 90 aaa cgatgaatgacgc cagacaaccg ccacaactgt agtacgacat cgttaatacg 349 Lys Argacttcagcaa acattttaac ataactgtgg ttgtgaagaa atcagttgct ttaaaagatt 409ggatttttcc ttgtttcaga gttgtactga tatgagctct gcaccatgaa ataaagctga 469agtgacgaac aaaaaaaaaa aaaaaaaaaa agtactctgc gttgttactc gagcttaagg 529gcgaattc 537 116 93 PRT Conus geographus 116 Met Gln Thr Ala Tyr Trp ValMet Leu Met Met Met Val Cys Ile Thr 1 5 10 15 Ala Pro Leu Pro Glu GlyGly Lys Pro Asn Ser Gly Ile Arg Gly Leu 20 25 30 Val Pro Asn Asp Leu ThrPro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Gln Thr Asp ValLeu Leu Glu Ala Thr Leu Leu Thr Thr Pro 50 55 60 Ala Pro Glu Gln Arg LeuPhe Cys Phe Trp Lys Ser Cys Thr Trp Arg 65 70 75 80 Pro Tyr Pro Trp ArgArg Arg Asp Leu Asn Gly Lys Arg 85 90 117 40 PRT Conus geographusPEPTIDE (1)..(40) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 7and 17 may be Glu or Gla; Xaa at residues 14, 16, 31 and 33 may be Proor hydroxy-Pro; Xaa at residues 24, 29 and 34 may be Trp (D or L) orbromo-Trp (D or L) 117 Xaa Thr Asp Val Leu Leu Xaa Ala Thr Leu Leu ThrThr Xaa Ala Xaa 1 5 10 15 Xaa Gln Arg Leu Phe Cys Phe Xaa Lys Ser CysThr Xaa Arg Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Arg Asp Leu Asn 35 40 118457 DNA Conus gladiator CDS (1)..(246) 118 atg cag acg gcc tac tgg gtgatg gtg atg atg atg gtg tgg gtt aca 48 Met Gln Thr Ala Tyr Trp Val MetVal Met Met Met Val Trp Val Thr 1 5 10 15 gtc cct cga tct gaa ggt ggcacg tgg aac tac tta att cgg ggt ttg 96 Val Pro Arg Ser Glu Gly Gly ThrTrp Asn Tyr Leu Ile Arg Gly Leu 20 25 30 gtg cca gac gac cta acc cca cagctt acc ttg cat cgt ctg gtt acc 144 Val Pro Asp Asp Leu Thr Pro Gln LeuThr Leu His Arg Leu Val Thr 35 40 45 cgt cgt cat cct gcc aac gtt aga cagcag ggg aaa ata tgt gta tgg 192 Arg Arg His Pro Ala Asn Val Arg Gln GlnGly Lys Ile Cys Val Trp 50 55 60 aag gtg tgt cca cca tgg cca gta aga tcacct ggt cca cag cca aaa 240 Lys Val Cys Pro Pro Trp Pro Val Arg Ser ProGly Pro Gln Pro Lys 65 70 75 80 aac aaa tgacgtcaga caaccgccac aactttagtacgacatcgtt gatacaactt 296 Asn Lys cagcaagtat tttaacatca ctgtggctctgaagaaatca gttgctttaa aagattggat 356 ttttccttgt tttagagttt tactgatatcagctctgcac tatgaaataa agatgtgacg 416 aaaaaaaaaa aaaaaaaaag tactctgcgttgttactcga g 457 119 82 PRT Conus gladiator 119 Met Gln Thr Ala Tyr TrpVal Met Val Met Met Met Val Trp Val Thr 1 5 10 15 Val Pro Arg Ser GluGly Gly Thr Trp Asn Tyr Leu Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp LeuThr Pro Gln Leu Thr Leu His Arg Leu Val Thr 35 40 45 Arg Arg His Pro AlaAsn Val Arg Gln Gln Gly Lys Ile Cys Val Trp 50 55 60 Lys Val Cys Pro ProTrp Pro Val Arg Ser Pro Gly Pro Gln Pro Lys 65 70 75 80 Asn Lys 120 32PRT Conus gladiator PEPTIDE (1)..(32) Xaa at residues 3, 18, 19, 21, 25,27 and 29 may be Pro or hydroxy-Pro; Xaa at residues 14 and 20 may beTrp (D or L) or bromo-Trp (D or L) 120 His Xaa Ala Asn Val Arg Gln GlnGly Lys Ile Cys Val Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Xaa Xaa Val ArgSer Xaa Gly Xaa Gln Xaa Lys Asn Lys 20 25 30 121 459 DNA Conus gladiatorCDS (1)..(246) 121 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtgtgg gtt aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val TrpVal Thr 1 5 10 15 gtc cct cga tct gaa ggt ggc acg tgg aac tac tta attcgg ggt ttg 96 Val Pro Arg Ser Glu Gly Gly Thr Trp Asn Tyr Leu Ile ArgGly Leu 20 25 30 gtg cca gac gac cta acc cca cag ctt acc ttg cat cgt ctggtt acc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Thr Leu His Arg Leu ValThr 35 40 45 cgt cgt cat cct gcc aac gtt aga cag cag ggg aaa ata tgt gtatgg 192 Arg Arg His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp50 55 60 aag gtg tgt cca cca tcg cca gta aga tca cct ggt cca ctg cca aaa240 Lys Val Cys Pro Pro Ser Pro Val Arg Ser Pro Gly Pro Leu Pro Lys 6570 75 80 aac aaa tgacgtcaga caaccgccac aactttagta cgacatcgtt gatacaactt296 Asn Lys cagcaagtat tttaacatca ctgtggctct gaagaaatca gttgctttaaaagattggat 356 ttttccttgt tttagagttt tactgatatc agctctgcac tatgaaataaagatgtgacg 416 gacaaaaaaa aaaaaaaaaa agtactctgc gttgttactc gag 459 12282 PRT Conus gladiator 122 Met Gln Thr Ala Tyr Trp Val Met Val Met MetMet Val Trp Val Thr 1 5 10 15 Val Pro Arg Ser Glu Gly Gly Thr Trp AsnTyr Leu Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu ThrLeu His Arg Leu Val Thr 35 40 45 Arg Arg His Pro Ala Asn Val Arg Gln GlnGly Lys Ile Cys Val Trp 50 55 60 Lys Val Cys Pro Pro Ser Pro Val Arg SerPro Gly Pro Leu Pro Lys 65 70 75 80 Asn Lys 123 32 PRT Conus gladiatorPEPTIDE (1)..(32) Xaa at residues 2, 18, 19, 21, 25, 27 and 29 may bePro or hydroxy-Pro; Xaa at residue 14 may be Trp (D or L) or bromo-Trp(D or L) 123 His Xaa Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Xaa LysVal 1 5 10 15 Cys Xaa Xaa Ser Xaa Val Arg Ser Xaa Gly Xaa Leu Xaa LysAsn Lys 20 25 30 124 499 DNA Conus litoglyphus CDS (21)..(254) 124gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 MetGln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcccct ctg tct gaa ggt gat aaa ttg aac gac 101 Met Val Trp Ile Thr Ala ProLeu Ser Glu Gly Asp Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg ccagat aac tta gcc cca cag ctt gtt ttg 149 Val Ile Arg Gly Leu Val Pro AspAsn Leu Ala Pro Gln Leu Val Leu 30 35 40 caa agt ctg gat tcc cgt cgt catcct cac ggc att cgt cag gat gga 197 Gln Ser Leu Asp Ser Arg Arg His ProHis Gly Ile Arg Gln Asp Gly 45 50 55 gcc caa ata tgt atc tgg aag ata tgtcca cca tcc cca tgg aga cga 245 Ala Gln Ile Cys Ile Trp Lys Ile Cys ProPro Ser Pro Trp Arg Arg 60 65 70 75 ctt gga tct taagaaaaga aacaattgacgtcagacaac cgccacatct 294 Leu Gly Ser tgagtacgac atcgttaata cgacttcagcaaatatgaaa ttttcagcat cactgtggtt 354 gtgaagaaat cagttgcttt aaaagattggatttgtcctt gtttaagagt tgtactgatg 414 tcatctctgc actatgaaat aaagctgatgtgaaaaaaaa aaaaaaaagt actctgcgtt 474 gttactcgag cttaagggcg aattc 499 12578 PRT Conus litoglyphus 125 Met Gln Thr Ala Tyr Trp Val Met Val Met MetMet Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu AsnAsp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu ValLeu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln AspGly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp ArgArg Leu Gly Ser 65 70 75 126 28 PRT Conus litoglyphus PEPTIDE (1)..(28)Xaa at residues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa atresidues 15 and 23 may be Trp (D or L) or bromo-Trp (D or L) 126 His XaaHis Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 IleCys Xaa Xaa Ser Xaa Xaa Arg Arg Leu Gly Ser 20 25 127 507 DNA Conuslitoglyphus CDS (21)..(254) 127 gaattcgccc ttatggatcc atg cag acg gcctac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val MetMet 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt gat aaa ttg aacgac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp15 20 25 gta att cgg ggt ttg gtg cca gat aac tta gcc cca cag ctt gtt ttg149 Val Ile Arg Gly Leu Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu 3035 40 caa agt ctg gat tcc cgt cgt cat cct cac ggc att cgt cag gat gga197 Gln Ser Leu Asp Ser Arg Arg His Pro His Gly Ile Arg Gln Asp Gly 4550 55 gcc caa ata tgt atc tgg aag ata tgt cca cca tcc cca tgg aaa cga245 Ala Gln Ile Cys Ile Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg 6065 70 75 ctt gga tct taagaaaaga aacaattgac gtcagacaac cgccacaact 294 LeuGly Ser tgagtacgac atcgttaata caacttcagc aaatatgaaa ttttcagcatcactgtggtt 354 gtgaagaaat cagttgcttt aaaggattgg atttgtcctt gtttaagagttgtactgatg 414 tcatctctgc actatgaaat aaagctgatg tgacaagcaa aaaaaaaaaaaaaaaagtac 474 tctgcgttgt tactcgagct taagggcgaa ttc 507 128 78 PRT Conuslitoglyphus 128 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val TrpIle Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val IleArg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu Gln SerLeu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala GlnIle Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu GlySer 65 70 75 129 28 PRT Conus litoglyphus PEPTIDE (1)..(28) Xaa atresidues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15and 23 may be Trp (D or L) or bromo-Trp (D or L) 129 His Xaa His Gly IleArg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa XaaSer Xaa Xaa Lys Arg Leu Gly Ser 20 25 130 507 DNA Conus litteratus CDS(21)..(299) 130 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atggtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atggtg ggg att aca gcc cct ctg tct gaa ggt cgt aaa ttg aac gac 101 Met ValGly Ile Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu Asn Asp 15 20 25 gca attcgg ggt ttg gtg cca gat gac tta acc cca cag ctt ttg cga 149 Ala Ile ArgGly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Leu Arg 30 35 40 agt ccg gtttcg act cct tat cct gag ttt cat ctt gat gaa cct tat 197 Ser Pro Val SerThr Pro Tyr Pro Glu Phe His Leu Asp Glu Pro Tyr 45 50 55 ctg aag ata cccgta tgt atc tgg aag ata tgt cca cca aac cta ttg 245 Leu Lys Ile Pro ValCys Ile Trp Lys Ile Cys Pro Pro Asn Leu Leu 60 65 70 75 aga cga cgt gatctt aag aaa aga aac aaa gta cgt cag aca acc gcc 293 Arg Arg Arg Asp LeuLys Lys Arg Asn Lys Val Arg Gln Thr Thr Ala 80 85 90 aca act tgagtacgacatcgttcata caacttgagc aaatatttca gcatcactat 349 Thr Thr ggttgtgaagaaatcagttg ctttaaaaga ttggatcttt ccttgtttaa gagttgtatt 409 gatgtcagctctgcactctg aaataaagct gatgtgacaa acaaaaaaaa aaaaaaaaaa 469 agtactctgcgttgttactc gagcttaagg gcgaattc 507 131 93 PRT Conus litteratus 131 MetGln Thr Ala Tyr Trp Val Met Val Met Met Met Val Gly Ile Thr 1 5 10 15Ala Pro Leu Ser Glu Gly Arg Lys Leu Asn Asp Ala Ile Arg Gly Leu 20 25 30Val Pro Asp Asp Leu Thr Pro Gln Leu Leu Arg Ser Pro Val Ser Thr 35 40 45Pro Tyr Pro Glu Phe His Leu Asp Glu Pro Tyr Leu Lys Ile Pro Val 50 55 60Cys Ile Trp Lys Ile Cys Pro Pro Asn Leu Leu Arg Arg Arg Asp Leu 65 70 7580 Lys Lys Arg Asn Lys Val Arg Gln Thr Thr Ala Thr Thr 85 90 132 50 PRTConus litteratus PEPTIDE (1)..(50) Xaa at residues 2, 6, 8, 15, 20, 28and 29 may be Pro or hydroxy-Pro; Xaa at residues 7 and 16 may be Tyr,125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaaat residues 9 and 14 may be Glu or Gla 132 Ser Xaa Val Ser Thr Xaa XaaXaa Xaa Phe His Leu Asp Xaa Xaa Xaa 1 5 10 15 Leu Lys Ile Xaa Val CysIle Xaa Lys Ile Cys Xaa Xaa Asn Leu Leu 20 25 30 Arg Arg Arg Asp Leu LysLys Arg Asn Lys Val Arg Gln Thr Thr Ala 35 40 45 Thr Thr 50 133 508 DNAConus litteratus CDS (21)..(275) 133 gaattcgccc ttatggatcc atg cag acggcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met ValMet Met 1 5 10 atg gtg ggg att aca gcc cct ctg tct gaa ggt cgt aaa ttgaac gac 101 Met Val Gly Ile Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu AsnAsp 15 20 25 gca att cgg ggt ttg gtg cca aat gac tta acc cca cag ctt ttgcaa 149 Ala Ile Arg Gly Leu Val Pro Asn Asp Leu Thr Pro Gln Leu Leu Gln30 35 40 agt ctg gtt tcc cgt cgt cat cgt gtg ttt cat ctt gac aac act tat197 Ser Leu Val Ser Arg Arg His Arg Val Phe His Leu Asp Asn Thr Tyr 4550 55 ctc aag ata ccc ata tgt gcc tgg aag gta tgt cca cca acc cca tgg245 Leu Lys Ile Pro Ile Cys Ala Trp Lys Val Cys Pro Pro Thr Pro Trp 6065 70 75 aga cga cgt gat ctt aag aaa aga aac aaa tgacgtcaga caaccgccac295 Arg Arg Arg Asp Leu Lys Lys Arg Asn Lys 80 85 aacttgagta cgacattgttaatgcgactt gagcaaattt ttcagcatca ctatggttgt 355 aaagaaatca gctgctttaaacgattggat ctttccttat ttaagagttg tattgatgtc 415 agctctgcac tctgaaataaagctgatgtg acaaacaaaa aaaaaaaaaa aaaaaagtac 475 tctgcgttgt tactcgagcttaagggcgaa ttc 508 134 85 PRT Conus litteratus 134 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Gly Ile Thr 1 5 10 15 Ala Pro Leu SerGlu Gly Arg Lys Leu Asn Asp Ala Ile Arg Gly Leu 20 25 30 Val Pro Asn AspLeu Thr Pro Gln Leu Leu Gln Ser Leu Val Ser Arg 35 40 45 Arg His Arg ValPhe His Leu Asp Asn Thr Tyr Leu Lys Ile Pro Ile 50 55 60 Cys Ala Trp LysVal Cys Pro Pro Thr Pro Trp Arg Arg Arg Asp Leu 65 70 75 80 Lys Lys ArgAsn Lys 85 135 36 PRT Conus litteratus PEPTIDE (1)..(36) Xaa at residue10 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr orO-phospho-Tyr; Xaa at residues 14, 22, 23 and 25 may be Pro orhydroxy-Pro; Xaa at residues 18 and 26 may be Trp (D or L) or bromo-Trp(D or L) 135 His Arg Val Phe His Leu Asp Asn Thr Xaa Leu Lys Ile Xaa IleCys 1 5 10 15 Ala Xaa Lys Val Cys Xaa Xaa Thr Xaa Xaa Arg Arg Arg AspLeu Lys 20 25 30 Lys Arg Asn Lys 35 136 498 DNA Conus loroisii CDS(21)..(236) misc_feature (1)..(498) n may be any base 136 gaattcgcccttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln ThrAla Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aaa ggc cct gtgtct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Lys Gly Pro Val SerGlu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca gac gactta acc cca cag ctt atc ttg 149 Val Ile Arg Gly Leu Val Pro Asp Asp LeuThr Pro Gln Leu Ile Leu 30 35 40 caa agt ctg atg tcc cgt cgt cgt tct gacagc gat gtt cgg gag gtg 197 Gln Ser Leu Met Ser Arg Arg Arg Ser Asp SerAsp Val Arg Glu Val 45 50 55 tac ata tta tgc atc tgg aag ata tgt cca ccattg cca tgaagacgac 246 Tyr Ile Leu Cys Ile Trp Lys Ile Cys Pro Pro LeuPro 60 65 70 atgatcttaa ggaaaaggat aaacgacgtc agacaaccgc tacaactgtagtacgacatc 306 gttaatacga cttcagcaaa tatttgaaca tcactgtggt tgtgaagaaatcagttgctt 366 taaacgattg gatttttcct taagagttgc actgatatca gctctgcactatgaaataaa 426 gctgatgtga ctaccaaaaa aaaaaaaaaa aaaaagtact ntgcgttgttactcgagctt 486 aagggcgaat tc 498 137 72 PRT Conus loroisii misc_feature(1)..(498) n may be any base 137 Met Gln Thr Ala Tyr Trp Val Met Val MetMet Met Val Trp Ile Lys 1 5 10 15 Gly Pro Val Ser Glu Gly Gly Lys LeuAsn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln LeuIle Leu Gln Ser Leu Met Ser 35 40 45 Arg Arg Arg Ser Asp Ser Asp Val ArgGlu Val Tyr Ile Leu Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Leu Pro 6570 138 22 PRT Conus loroisii PEPTIDE (1)..(22) Xaa at residue 8 may beGlu or Gla; Xaa at residue 10 may be Tyr, 125I-Tyr, mono-iodo-Tyr,di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residue 15 may be Trp(D or L) or bromo-Trp (D or L); Xaa at residues 19, 20 and 22 may be Proor hydroxy-Pro 138 Arg Ser Asp Ser Asp Val Arg Xaa Val Xaa Ile Leu CysIle Xaa Lys 1 5 10 15 Ile Cys Xaa Xaa Leu Xaa 20 139 495 DNA Conus magusCDS (21)..(242) 139 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtgatg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 MetVal Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gtaatt cgg ggt ttg gtg cca cac tcc tta acc cca cag cat atc ttg 149 Val IleArg Gly Leu Val Pro His Ser Leu Thr Pro Gln His Ile Leu 30 35 40 caa agtctg act tcc cgt aat ggt tct ggc agc agc aat cag aaa gaa 197 Gln Ser LeuThr Ser Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu 45 50 55 gca caa ctatgc atc tgg aag gta tgt cca cca tcc cca tgg aga 242 Ala Gln Leu Cys IleTrp Lys Val Cys Pro Pro Ser Pro Trp Arg 60 65 70 tgaccacaag gaaaaagatgaacggcgtca gacaaccgcc acaactgtag tgggacatcg 302 ttgatacgac ttcaacaaatattttaacat cactgtggtt gtaaagaaat cagttgcttt 362 aaaagattgg atttttccttgtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaaacaaaaaaaaaaaa aaaaaagtac tctgcgttgt tactcgagct 482 taagggcgaa ttc 495 14074 PRT Conus magus 140 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetVal Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn AspVal Ile Arg Gly Leu 20 25 30 Val Pro His Ser Leu Thr Pro Gln His Ile LeuGln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys GluAla Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg 6570 141 25 PRT Conus magus PEPTIDE (1)..(25) Xaa at residue 10 may be Gluor Gla; Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D orL); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 141 Asn GlySer Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu Cys Ile Xaa 1 5 10 15 LysVal Cys Xaa Xaa Ser Xaa Xaa Arg 20 25 142 587 DNA Conus miles CDS(21)..(347) misc_feature (1)..(587) n may be any nucleotide 142gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg gtg 53 MetGln Thr Ala Tyr Trp Val Met Met Met Val 1 5 10 gtg atg atg gtg ggg gttact gtc gct ggc tcc ctg cct gtg ttt gat 101 Val Met Met Val Gly Val ThrVal Ala Gly Ser Leu Pro Val Phe Asp 15 20 25 gac gac aac gac tct gac cccgct gtc aag cgc gct atc acg tgg tcc 149 Asp Asp Asn Asp Ser Asp Pro AlaVal Lys Arg Ala Ile Thr Trp Ser 30 35 40 cgc atc ctg ggc gtg tct cca gccttc ctg gca cag cag cga gcg ctg 197 Arg Ile Leu Gly Val Ser Pro Ala PheLeu Ala Gln Gln Arg Ala Leu 45 50 55 gtt ccc ttc gcc aac cga ttc atc agtgag cag aaa cgt ttc cga ccc 245 Val Pro Phe Ala Asn Arg Phe Ile Ser GluGln Lys Arg Phe Arg Pro 60 65 70 75 gcc atg cag agc cga tca gga gga atgtcg ctg tgc cta tgg aaa gtg 293 Ala Met Gln Ser Arg Ser Gly Gly Met SerLeu Cys Leu Trp Lys Val 80 85 90 tgt cct gca gcc ccc tgg ctg gtc gcc aaacgt aaa cag gaa acc agc 341 Cys Pro Ala Ala Pro Trp Leu Val Ala Lys ArgLys Gln Glu Thr Ser 95 100 105 gac tac tgacgtcata cctctaaaga cccactcatgacgtcaacgc tgaactgacg 397 Asp Tyr tcaccgacag ctccaacgtc acagcaggagcgagagagag gctggagcat ttctctttct 457 tttggttttt cgagttgaag tgtgatcagctgggctggtg aaaaaattgt tgagtaaagt 517 tgaatgaaaa tcaaaaaaaa aaaaaaaaaaagtactctgc gttggtactc gaggcttaaa 577 ggcgnaattc 587 143 109 PRT Conusmiles misc_feature (1)..(587) n may be any nucleotide 143 Met Gln ThrAla Tyr Trp Val Met Met Met Val Val Met Met Val Gly 1 5 10 15 Val ThrVal Ala Gly Ser Leu Pro Val Phe Asp Asp Asp Asn Asp Ser 20 25 30 Asp ProAla Val Lys Arg Ala Ile Thr Trp Ser Arg Ile Leu Gly Val 35 40 45 Ser ProAla Phe Leu Ala Gln Gln Arg Ala Leu Val Pro Phe Ala Asn 50 55 60 Arg PheIle Ser Glu Gln Lys Arg Phe Arg Pro Ala Met Gln Ser Arg 65 70 75 80 SerGly Gly Met Ser Leu Cys Leu Trp Lys Val Cys Pro Ala Ala Pro 85 90 95 TrpLeu Val Ala Lys Arg Lys Gln Glu Thr Ser Asp Tyr 100 105 144 37 PRT Conusmiles PEPTIDE (1)..(37) Xaa at residues 3, 21 and 24 may be Pro orhydroxy-Pro; Xaa at residues 17 and 25 may be Trp (D or L) or bromo-Trp(D or L); Xaa at residue 33 may be Glu or Gla; 144 Phe Arg Xaa Ala MetGln Ser Arg Ser Gly Gly Met Ser Leu Cys Leu 1 5 10 15 Xaa Lys Val CysXaa Ala Ala Xaa Xaa Leu Val Ala Lys Arg Lys Gln 20 25 30 Xaa Thr Ser AspXaa 35 145 499 DNA Conus miles CDS (21)..(401) 145 gaattcgccc ttatggatccatg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr TrpVal Met Val Met Met 1 5 10 atg gtg gtg ggt tca ccg tcg gga gtc acg tccatc ggt ctc aca gtc 101 Met Val Val Gly Ser Pro Ser Gly Val Thr Ser IleGly Leu Thr Val 15 20 25 cta cgt cgc gca acc atg gtg atg act cca ttc atgaca aga cga ttc 149 Leu Arg Arg Ala Thr Met Val Met Thr Pro Phe Met ThrArg Arg Phe 30 35 40 atc aac atc tgt ttg ccc gtc ttc ctc tgg aga aca acgacg acc atc 197 Ile Asn Ile Cys Leu Pro Val Phe Leu Trp Arg Thr Thr ThrThr Ile 45 50 55 gtt ctg tgg atc ttc ctg cag tgt atg cgc cgg gcc agg cacgtg tgc 245 Val Leu Trp Ile Phe Leu Gln Cys Met Arg Arg Ala Arg His ValCys 60 65 70 75 gtt cta ctt ttg ttc ttg acc tca ttg cag ata ggg gtt ggtgca gac 293 Val Leu Leu Leu Phe Leu Thr Ser Leu Gln Ile Gly Val Gly AlaAsp 80 85 90 gac atg aaa cta cag cgc caa aga cgt caa ggt ttc tgt tgc gtcgtt 341 Asp Met Lys Leu Gln Arg Gln Arg Arg Gln Gly Phe Cys Cys Val Val95 100 105 atc ccg att ctt tgg ttc tgt tgt ggg ggt tac cgc aca aat ggcact 389 Ile Pro Ile Leu Trp Phe Cys Cys Gly Gly Tyr Arg Thr Asn Gly Thr110 115 120 gca ctg gcc gat tgaaagaact gcaataaacg gaatggcaag aaggaataaa441 Ala Leu Ala Asp 125 aaaaaaaaaa aaaaaaaaaa agtactctgc gttgttactcgagcttaagg gcgaattc 499 146 127 PRT Conus miles 146 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Val Gly Ser 1 5 10 15 Pro Ser Gly ValThr Ser Ile Gly Leu Thr Val Leu Arg Arg Ala Thr 20 25 30 Met Val Met ThrPro Phe Met Thr Arg Arg Phe Ile Asn Ile Cys Leu 35 40 45 Pro Val Phe LeuTrp Arg Thr Thr Thr Thr Ile Val Leu Trp Ile Phe 50 55 60 Leu Gln Cys MetArg Arg Ala Arg His Val Cys Val Leu Leu Leu Phe 65 70 75 80 Leu Thr SerLeu Gln Ile Gly Val Gly Ala Asp Asp Met Lys Leu Gln 85 90 95 Arg Gln ArgArg Gln Gly Phe Cys Cys Val Val Ile Pro Ile Leu Trp 100 105 110 Phe CysCys Gly Gly Tyr Arg Thr Asn Gly Thr Ala Leu Ala Asp 115 120 125 147 27PRT Conus miles PEPTIDE (1)..(27) Xaa at residue 1 is Gln or pyro-Glu;Xaa at residue 9 may be Pro or hydroxy-Pro; Xaa at residue 12 may be Trp(D or L) or bromo-Trp (D or L); Xaa at residue 18 may be Tyr, 125I-Tyr,mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 147 Xaa GlyPhe Cys Cys Val Val Ile Xaa Ile Leu Xaa Phe Cys Cys Gly 1 5 10 15 GlyXaa Arg Thr Asn Gly Thr Ala Leu Ala Asp 20 25 148 450 DNA Conusmuriculatus CDS (1)..(237) 148 atg cag acg gcc tac tgg gtg atg gtg atgatg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met MetMet Val Trp Ile Thr 1 5 10 15 gcc cct ttg tct gaa ggt ggt aaa ctg aacgat gta att cgg ggt ttc 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn AspVal Ile Arg Gly Phe 20 25 30 gcg cta gat gac tta gcc caa agc cgt att atgcaa agt ctg gtt ttc 144 Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met GlnSer Leu Val Phe 35 40 45 agt cat cag cct ctt cca acg gca tcc ata tgt atctgg aag ata tgt 192 Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys Ile TrpLys Ile Cys 50 55 60 cca cca gac cca tgg aga cga cat gat ctt cag aaa agtaac aaa 237 Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln Lys Ser Asn Lys65 70 75 tgacgtcaga caaccgccac aacttgaata caacatcatt aatacgacttcagcaaatat 297 tttaacatca ctgtgattgt tcggaagtca gttgctttaa aggattggatttgtccctgt 357 tgtattgatg tcaactctgc actatgaaat aaagctgatg tgacaaacaagaaaaaaaaa 417 aaaaaaaaaa agtactctgc gttgttactc gag 450 149 79 PRT Conusmuriculatus 149 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val TrpIle Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val IleArg Gly Phe 20 25 30 Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met Gln SerLeu Val Phe 35 40 45 Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys Ile TrpLys Ile Cys 50 55 60 Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln Lys SerAsn Lys 65 70 75 150 38 PRT Conus muriculatus PEPTIDE (1)..(38) Xaa atresidues 11, 13, 24, 25 and 27 may be Pro or hydroxy-Pro; Xaa at residue20 and 28 may be Trp or bromo-Trp 150 Ile Met Gln Ser Leu Val Phe SerHis Gln Xaa Leu Xaa Thr Ala Ser 1 5 10 15 Ile Cys Ile Xaa Lys Ile CysXaa Xaa Asp Xaa Xaa Arg Arg His Asp 20 25 30 Leu Gln Lys Ser Asn Lys 35151 437 DNA Conus musicus CDS (1)..(240) 151 atg cag acg gcc tac tgg gtgatg atg atg acg atg atg gtg tgg atg 48 Met Gln Thr Ala Tyr Trp Val MetMet Met Thr Met Met Val Trp Met 1 5 10 15 aca gcc cct ctg tct gaa ggtcgt cca ctg agc gac gaa gtt cgg ggt 96 Thr Ala Pro Leu Ser Glu Gly ArgPro Leu Ser Asp Glu Val Arg Gly 20 25 30 atg gtg cca ggc gac ttg gtc ctacag tat ctg ttc cca agt ctg gct 144 Met Val Pro Gly Asp Leu Val Leu GlnTyr Leu Phe Pro Ser Leu Ala 35 40 45 ttc agt cct ccg gac ata tgt acg tggaag gta tgt cca cca ccc cca 192 Phe Ser Pro Pro Asp Ile Cys Thr Trp LysVal Cys Pro Pro Pro Pro 50 55 60 tgg aga cga cca aaa aaa ata aca gac gtcaga cag ccg cca caa ctg 240 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val ArgGln Pro Pro Gln Leu 65 70 75 80 tagtacgaca tcgttgatac ggcttcagcaaatattttca acatcactgc ggttgtgaag 300 aaatcagttg ctttaaaatg ttggatttttccttgtttaa aagagctgta ctgatgtcag 360 ccctgcatta cgaaataaag ctgatgtgacaaacaaaaaa aaaaaaaaaa aaaaagtact 420 ctgcgttgtt actcgag 437 152 80 PRTConus musicus 152 Met Gln Thr Ala Tyr Trp Val Met Met Met Thr Met MetVal Trp Met 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser AspGlu Val Arg Gly 20 25 30 Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu PhePro Ser Leu Ala 35 40 45 Phe Ser Pro Pro Asp Ile Cys Thr Trp Lys Val CysPro Pro Pro Pro 50 55 60 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg GlnPro Pro Gln Leu 65 70 75 80 153 49 PRT Conus musicus PEPTIDE (1)..(49)Xaa at residues 4, 14, 20, 21, 30, 31, 32, 33, 37, 46 and 47 may be Proor hydroxy-Pro; Xaa at residue 11 may be Tyr, 125I-Tyr, mono-iodo-Tyr,di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 26 and 34may be Trp (D or L) or bromo-Trp (D or L) 153 Gly Met Val Xaa Gly AspLeu Val Leu Gln Xaa Leu Phe Xaa Ser Leu 1 5 10 15 Ala Phe Ser Xaa XaaAsp Ile Cys Thr Xaa Lys Val Cys Xaa Xaa Xaa 20 25 30 Xaa Xaa Arg Arg XaaLys Lys Ile Thr Asp Val Arg Gln Xaa Xaa Gln 35 40 45 Leu 154 436 DNAConus musicus CDS (1)..(216) 154 atg cag acg gcc tac tgg gtg atg atg atgatg atg atg gtg tgg atg 48 Met Gln Thr Ala Tyr Trp Val Met Met Met MetMet Met Val Trp Met 1 5 10 15 aca gcc cct ctg tct gaa ggt cgt aaa ctgatc gac aaa gtt cgg ggt 96 Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu IleAsp Lys Val Arg Gly 20 25 30 atg ggg cca ggc gac tta tcc cta cag aaa atgttc cca agt ctg gct 144 Met Gly Pro Gly Asp Leu Ser Leu Gln Lys Met PhePro Ser Leu Ala 35 40 45 tta ggt cct ggg gga gac gta ata tgt agg tgg aaggta tgt cca cca 192 Leu Gly Pro Gly Gly Asp Val Ile Cys Arg Trp Lys ValCys Pro Pro 50 55 60 acc cca tgg aaa cga cta ata aaa taactgacgtcagacagccg ccacaactgt 246 Thr Pro Trp Lys Arg Leu Ile Lys 65 70agtacgacat cgttgatacg acttcagcaa atatttcaac atcactgcgg ttgtgaagaa 306atcagttgct ttaaaagatt ggatttttcc ttgtttaaag agttgtactg atatcagctc 366tgcattacga aataaagctg atgtgacaaa caaaaaaaaa aaaaaaaagt actctgcgtt 426gttactcgag 436 155 72 PRT Conus musicus 155 Met Gln Thr Ala Tyr Trp ValMet Met Met Met Met Met Val Trp Met 1 5 10 15 Thr Ala Pro Leu Ser GluGly Arg Lys Leu Ile Asp Lys Val Arg Gly 20 25 30 Met Gly Pro Gly Asp LeuSer Leu Gln Lys Met Phe Pro Ser Leu Ala 35 40 45 Leu Gly Pro Gly Gly AspVal Ile Cys Arg Trp Lys Val Cys Pro Pro 50 55 60 Thr Pro Trp Lys Arg LeuIle Lys 65 70 156 41 PRT Conus musicus PEPTIDE (1)..(41) Xaa at residues4, 14, 20, 32, 33 and 35 may be Pro or hydroxy-Pro; Xaa at residues 28and 36 may be Trp (D or L) or bromo-Trp (D or L) 156 Gly Met Gly Xaa GlyAsp Leu Ser Leu Gln Lys Met Phe Xaa Ser Leu 1 5 10 15 Ala Leu Gly XaaGly Gly Asp Val Ile Cys Arg Xaa Lys Val Cys Xaa 20 25 30 Xaa Thr Xaa XaaLys Arg Leu Ile Lys 35 40 157 449 DNA Conus musicus CDS (1)..(243) 157atg cag acg gcc tac tgg gtg atg atg atg atg acg atg atg gtg tgg 48 MetGln Thr Ala Tyr Trp Val Met Met Met Met Thr Met Met Val Trp 1 5 10 15atg aca gcc cct ctg tct gaa ggt cgt cca ctg agc gac aaa gtt cgg 96 MetThr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg 20 25 30 ggtatg gtg cca ggc gac tta gcc ctg cag tat ctg ttc cca agt ctg 144 Gly MetVal Pro Gly Asp Leu Ala Leu Gln Tyr Leu Phe Pro Ser Leu 35 40 45 gct ttcaat ccc ccg gac ata tgt acg tgg aag gta tgt cca cca ccc 192 Ala Phe AsnPro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 50 55 60 cca tgg agacga cca aaa aaa ata act gac gtc gga cag ccg cca caa 240 Pro Trp Arg ArgPro Lys Lys Ile Thr Asp Val Gly Gln Pro Pro Gln 65 70 75 80 ctgtagtacgaca tcgttgatac gacttcagca aatattttca acatcactgc 293 Leuggttgtgaag aaatcagttg ttttaaaagg ttggattttt ccttgtttaa aagagctgta 353ctgatgtcag ctctgcatta cgaaataaag ctgatgtgac aaacgaaaaa aaaaaaaaaa 413aaaaaaaaaa aaaagtactc tgcgttgtta ctcgag 449 158 81 PRT Conus musicus 158Met Gln Thr Ala Tyr Trp Val Met Met Met Met Thr Met Met Val Trp 1 5 1015 Met Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg 20 2530 Gly Met Val Pro Gly Asp Leu Ala Leu Gln Tyr Leu Phe Pro Ser Leu 35 4045 Ala Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 50 5560 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Gly Gln Pro Pro Gln 65 7075 80 Leu 159 49 PRT Conus musicus PEPTIDE (1)..(49) Xaa at residues 4,14, 20, 21, 30, 31, 32, 33, 37, 46 and 47 may be Pro or hydroxy-Pro; Xaaat residue 11 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr,O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 26 and 34 may be Trp (Dor L) or bromo-Trp (D or L) 159 Gly Met Val Xaa Gly Asp Leu Ala Leu GlnXaa Leu Phe Xaa Ser Leu 1 5 10 15 Ala Phe Asn Xaa Xaa Asp Ile Cys ThrXaa Lys Val Cys Xaa Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Xaa Lys Lys Ile ThrAsp Val Gly Gln Xaa Xaa Gln 35 40 45 Leu 160 436 DNA Conus musicus CDS(1)..(240) 160 atg cag acg gcc tac tgg gtg atg atg atg acg atg atg gtgtgg atg 48 Met Gln Thr Ala Tyr Trp Val Met Met Met Thr Met Met Val TrpMet 1 5 10 15 aca gcc cct ctg tct gaa ggt cgt cca ctg agc gac aaa gttcgg ggt 96 Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val ArgGly 20 25 30 atg gtg cca ggc gac tta gtc ctg cag tat ctg ttc cca agt ctggct 144 Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu Ala35 40 45 ttc aat cct ccg gac ata tgt acg tgg aag gta tgt cca cca ccc cca192 Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro 5055 60 tgg aga cga cca aaa aaa ata act gac gtc aga cag ccg cca caa ctg240 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln Leu 6570 75 80 tagtacgaca tcgttgatac gacttcagca aatattttca acatcactgcggttgtgaag 300 aaatcagttg ttttaaaagg ttggattttt ccttgtttaa aagagctgtactgatgtcag 360 ctctgcatta cgaaataaag ctgatgtgac aagcaaaaaa aaaaaaaaaaaaaagtactc 420 tgcgttgtta ctcgag 436 161 80 PRT Conus musicus 161 MetGln Thr Ala Tyr Trp Val Met Met Met Thr Met Met Val Trp Met 1 5 10 15Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg Gly 20 25 30Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu Ala 35 40 45Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro 50 55 60Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln Leu 65 70 7580 162 49 PRT Conus musicus PEPTIDE (1)..(49) Xaa at residues 4, 14, 20,21, 30, 31, 32, 33, 37, 46 and 47 may be Pro or hydroxy-Pro; Xaa atresidue 11 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr,O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 26 and 34 may be Trp (Dor L) or bromo-Trp (D or L) 162 Gly Met Val Xaa Gly Asp Leu Val Leu GlnXaa Leu Phe Xaa Ser Leu 1 5 10 15 Ala Phe Asn Xaa Xaa Asp Ile Cys ThrXaa Lys Val Cys Xaa Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Xaa Lys Lys Ile ThrAsp Val Arg Gln Xaa Xaa Gln 35 40 45 Leu 163 462 DNA Conus mustelinusCDS (1)..(225) 163 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gcgtgg tat aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Ala TrpTyr Thr 1 5 10 15 acc cct gtg tct gaa tgt ggg aaa ttg aac aac gta attcgg ggt ttt 96 Thr Pro Val Ser Glu Cys Gly Lys Leu Asn Asn Val Ile ArgGly Phe 20 25 30 gtg cca aag gac tgg acc cca atg ctt ccc tgg cgt cgt ctagtt tcc 144 Val Pro Lys Asp Trp Thr Pro Met Leu Pro Trp Arg Arg Leu ValSer 35 40 45 cat acc agc agc aag tat cca ggt gtg act ttt tgt cca tgg aaggtg 192 His Thr Ser Ser Lys Tyr Pro Gly Val Thr Phe Cys Pro Trp Lys Val50 55 60 tgt ccg cca gcg cca tgg aga ata ctt ggg gtc taacgcaaaaaaatacatga 245 Cys Pro Pro Ala Pro Trp Arg Ile Leu Gly Val 65 70 75cgtcagacaa ccgccaccgc tttagtacga catcgttcat acgtctccag caagtatttt 305aacatcactg tggttgtgaa gaagtcagta gctttaaaag attggatttt ttccttgttt 365aagagttgta ctgacatgag ttctgcacta tgaaataaag ttgatgtgac gaacgaaaaa 425aaaaaaaaaa aaaaagtact ctgcgttgtt actcgag 462 164 75 PRT Conus mustelinus164 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Ala Trp Tyr Thr 1 510 15 Thr Pro Val Ser Glu Cys Gly Lys Leu Asn Asn Val Ile Arg Gly Phe 2025 30 Val Pro Lys Asp Trp Thr Pro Met Leu Pro Trp Arg Arg Leu Val Ser 3540 45 His Thr Ser Ser Lys Tyr Pro Gly Val Thr Phe Cys Pro Trp Lys Val 5055 60 Cys Pro Pro Ala Pro Trp Arg Ile Leu Gly Val 65 70 75 165 30 PRTConus mustelinus PEPTIDE (1)..(30) Xaa at residue 9 may be Tyr,125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaaat residues 10, 16, 21, 22 and 24 may be Pro or hydroxy-Pro; Xaa atresidues 17 and 25 may be Trp (D or L) or bromo-Trp (D or L) 165 Leu ValSer His Thr Ser Ser Lys Xaa Xaa Gly Val Thr Phe Cys Xaa 1 5 10 15 XaaLys Val Cys Xaa Xaa Ala Xaa Xaa Arg Ile Leu Gly Val 20 25 30 166 619 DNAConus nobilis CDS (21)..(350) 166 gaattcgccc ttatggatcc atg cag acg gcctac tgg gtg atg atg atg gtg 53 Met Gln Thr Ala Tyr Trp Val Met Met MetVal 1 5 10 gtg gtg atg atg gtg ggg gtt act gtc gct ggc tca ctg tct gtgttt 101 Val Val Met Met Val Gly Val Thr Val Ala Gly Ser Leu Ser Val Phe15 20 25 gat gat gac aac gac tct gac cca gct gtc aag cgc gcc atc acg tgg149 Asp Asp Asp Asn Asp Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp 3035 40 tct cga ttc ctg ggc gcg tct cca gcc ttc ctg gca cag cag cga gcg197 Ser Arg Phe Leu Gly Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala 4550 55 ctg gct ccc ttc gcc aac cga ccc atc aat gag cag aaa cgt ttc cga245 Leu Ala Pro Phe Ala Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg 6065 70 75 cct gcc gtg aag agc cga tca cga cga gcg ccg ccg tgc gtg tgg aag293 Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro Cys Val Trp Lys 8085 90 gtg tgt ccc gct ccc ccc tgg ctg gtc acc aaa cgt aaa cag gaa acc341 Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys Arg Lys Gln Glu Thr 95100 105 agc gac tac tgacgtcata cctcaataga ccgactcatg acttcaacgc 390 SerAsp Tyr 110 tgaattgacg tcaccgagag ctccaacgtc acagcaggag cgagagagagagagagagag 450 agagaaagag agagagaaag gctggagtat ttctctttct tttggtttttcgtgttgaag 510 tgtgatcagc tgggctggtt caaaattgtt gaataaagtt gaatgaaaatcaaaaaaaaa 570 aaaaaaaaaa aagtactctg cgttgttact cgagcttaag ggcgaattc 619167 110 PRT Conus nobilis 167 Met Gln Thr Ala Tyr Trp Val Met Met MetVal Val Val Met Met Val 1 5 10 15 Gly Val Thr Val Ala Gly Ser Leu SerVal Phe Asp Asp Asp Asn Asp 20 25 30 Ser Asp Pro Ala Val Lys Arg Ala IleThr Trp Ser Arg Phe Leu Gly 35 40 45 Ala Ser Pro Ala Phe Leu Ala Gln GlnArg Ala Leu Ala Pro Phe Ala 50 55 60 Asn Arg Pro Ile Asn Glu Gln Lys ArgPhe Arg Pro Ala Val Lys Ser 65 70 75 80 Arg Ser Arg Arg Ala Pro Pro CysVal Trp Lys Val Cys Pro Ala Pro 85 90 95 Pro Trp Leu Val Thr Lys Arg LysGln Glu Thr Ser Asp Tyr 100 105 110 168 37 PRT Conus nobilis PEPTIDE(1)..(37) Xaa at residues 3, 13, 14, 21, 23 and 24 may be Pro orhydroxy-Pro; Xaa at residues 17 and 25 may be Trp (D or L) or bromo-Trp(D or L); Xaa at residue 33 may be Glu or Gla; 168 Phe Arg Xaa Ala ValLys Ser Arg Ser Arg Arg Ala Xaa Xaa Cys Val 1 5 10 15 Xaa Lys Val CysXaa Ala Xaa Xaa Xaa Leu Val Thr Lys Arg Lys Gln 20 25 30 Xaa Thr Ser AspXaa 35 169 494 DNA Conus nobilis CDS (21)..(242) 169 gaattcgcccttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln ThrAla Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctgtct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu SerGlu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac ttctta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Phe LeuThr Pro Gln His Ile Leu 30 35 40 caa agt ctg act tcc cgt aat ggt tct ggcagc agt aat cag aaa gaa 197 Gln Ser Leu Thr Ser Arg Asn Gly Ser Gly SerSer Asn Gln Lys Glu 45 50 55 gcg caa cta tgc atc tgg aag gta tgt cca ccaacc cca tgg aga 242 Ala Gln Leu Cys Ile Trp Lys Val Cys Pro Pro Thr ProTrp Arg 60 65 70 tgatcacaag gaaaaagatg aacggcgtca gacaaccgcc acaactgtagtgggacatcg 302 ttgatacgac ttcagcaaat attttaacat cactgtggtt gtgaagaaatcagttgtttt 362 aaaagattgg atttttcctt gtttaagagt tgtactgata tcagctctgcactatgaaat 422 aaagctgatg tgacaagcaa aaaaaaaaaa aaaaagtact ctgcgttgttactcgagctt 482 aagggcgaat tc 494 170 74 PRT Conus nobilis 170 Met GlnThr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 AlaPro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 ValPro His Phe Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 ArgAsn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile 50 55 60 TrpLys Val Cys Pro Pro Thr Pro Trp Arg 65 70 171 25 PRT Conus nobilisPEPTIDE (1)..(25) Xaa at residue 10 may be Glu or Gla; Xaa at residues16 and 24 may be Trp or bromo-Trp; Xaa at residues 20, 21 and 23 may bePro or hydroxy-Pro 171 Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala GlnLeu Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Thr Xaa Xaa Arg 20 25 172604 DNA Conus nobilis CDS (21)..(350) 172 gaattcgccc ttatggatcc atg cagacg gcc tac tgg gtg atg atg atg gtg 53 Met Gln Thr Ala Tyr Trp Val MetMet Met Val 1 5 10 gtg gtg atg atg gtg ggg gtt act gtc gct ggc tca ctgtct gtg ttt 101 Val Val Met Met Val Gly Val Thr Val Ala Gly Ser Leu SerVal Phe 15 20 25 gat gac gac aat gac tct gac cca gct gtc aag cgc gcc atcacg tgg 149 Asp Asp Asp Asn Asp Ser Asp Pro Ala Val Lys Arg Ala Ile ThrTrp 30 35 40 tct cga ttc ctg ggc gcg tct cca gcc ttc ctg gca cag cag cgagcg 197 Ser Arg Phe Leu Gly Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala45 50 55 ctg gct ccc ttc gcc aac cga ccc atc aat gag cag aaa cgt ttc cga245 Leu Ala Pro Phe Ala Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg 6065 70 75 cct gcc gtg aag agc cga tca cga cga gcg ccg ccg tgc gta tgg aag293 Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro Cys Val Trp Lys 8085 90 gtg tgt ccc gct ccc ccc tgg ctg gtc acc aaa cgt aaa cag gaa acc341 Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys Arg Lys Gln Glu Thr 95100 105 agc gac tac tgacgtcata cctcaataga ccgactcatg acttcaacgc 390 SerAsp Tyr 110 tgaattgacc tcaccgagag ctccaacgtc acagcaggag cgagagagagagagagagag 450 agagagagag aaaggctgga gtatttctct ttctttcggt ttttcgtgttgaagtgtgat 510 cagctgggct ggttcaaaat tgttgaataa agttgaataa aaaaaaaaaaaaaaaaagta 570 ctctgcgttg ttactcgagc ttaagggcga attc 604 173 110 PRTConus nobilis 173 Met Gln Thr Ala Tyr Trp Val Met Met Met Val Val ValMet Met Val 1 5 10 15 Gly Val Thr Val Ala Gly Ser Leu Ser Val Phe AspAsp Asp Asn Asp 20 25 30 Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp SerArg Phe Leu Gly 35 40 45 Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala LeuAla Pro Phe Ala 50 55 60 Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg ProAla Val Lys Ser 65 70 75 80 Arg Ser Arg Arg Ala Pro Pro Cys Val Trp LysVal Cys Pro Ala Pro 85 90 95 Pro Trp Leu Val Thr Lys Arg Lys Gln Glu ThrSer Asp Tyr 100 105 110 174 37 PRT Conus nobilis PEPTIDE (1)..(37) Xaaat residues 3, 13, 14, 21, 23 and 24 may be Pro or hydroxy-Pro; Xaa atresidues 17 and 25 may be Trp (D or L) or bromo-Trp (D or L); Xaa atresidue 33 may be Glu or Gla; 174 Phe Arg Xaa Ala Val Lys Ser Arg SerArg Arg Ala Xaa Xaa Cys Val 1 5 10 15 Xaa Lys Val Cys Xaa Ala Xaa XaaXaa Leu Val Thr Lys Arg Lys Gln 20 25 30 Xaa Thr Ser Asp Xaa 35 175 391DNA Conus parius CDS (21)..(275) 175 gaattcgccc ttatggatcc atg cag acggcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met ValMet Met 1 5 10 atg gtg gtg tgg att aca gcc cct ttg tct gaa ggt ggt aaaccg aag 101 Met Val Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys ProLys 15 20 25 cac gca att cgg ggt ttg gtg cca gac gac tta acc cca cag cttatc 149 His Ala Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile30 35 40 ttg cga agt ctg att tcc cgt cgt agt tct ttc ggc aag gat gcg aaa197 Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Phe Gly Lys Asp Ala Lys 4550 55 ccc ccc ttt agt tgt tca ggc ctc cga ggg ggt tgc gtc cta cct ccc245 Pro Pro Phe Ser Cys Ser Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 6065 70 75 aat ctc agg cca aag ttc aac aaa ggt gga taacaaaccc aagcgttcct295 Asn Leu Arg Pro Lys Phe Asn Lys Gly Gly 80 85 agttatacga atgccagcaaataaaagcag tttgattgtg aaaaaaaaaa aaaaaaaaag 355 tactctgcgt tgttactcgagcttaagggc gaattc 391 176 85 PRT Conus parius 176 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Val Trp Ile 1 5 10 15 Thr Ala Pro LeuSer Glu Gly Gly Lys Pro Lys His Ala Ile Arg Gly 20 25 30 Leu Val Pro AspAsp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile 35 40 45 Ser Arg Arg SerSer Phe Gly Lys Asp Ala Lys Pro Pro Phe Ser Cys 50 55 60 Ser Gly Leu ArgGly Gly Cys Val Leu Pro Pro Asn Leu Arg Pro Lys 65 70 75 80 Phe Asn LysGly Gly 85 177 25 PRT Conus parius PEPTIDE (1)..(25) Xaa at residues 1,3, 15, 16 and 20 may be Pro or hydroxy-Pro 177 Xaa Xaa Phe Ser Cys SerGly Leu Arg Gly Gly Cys Val Leu Xaa Xaa 1 5 10 15 Asn Leu Arg Xaa LysPhe Asn Lys Gly 20 25 178 390 DNA Conus parius CDS (19)..(273) 178gaattcgccc ttggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 51 MetGln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg atg tgg att acagcc cct ctg tct gaa ggt ggt aaa ccg aag 99 Met Val Met Trp Ile Thr AlaPro Leu Ser Glu Gly Gly Lys Pro Lys 15 20 25 ctc ata att cgg ggt ttg gtgcca aac gac tta acc cca cag cgt atc 147 Leu Ile Ile Arg Gly Leu Val ProAsn Asp Leu Thr Pro Gln Arg Ile 30 35 40 ttg cga agt ctg att tcc ggg cgtact tat ggc atc tat gat gcg aaa 195 Leu Arg Ser Leu Ile Ser Gly Arg ThrTyr Gly Ile Tyr Asp Ala Lys 45 50 55 ccc ccc ttt agt tgt gca ggc ctc cgaggg ggt tgc gtc cta cct ccc 243 Pro Pro Phe Ser Cys Ala Gly Leu Arg GlyGly Cys Val Leu Pro Pro 60 65 70 75 aat ctc agg cca aag ttc aag gaa ggtcga taaaaaaccc aagcgttcct 293 Asn Leu Arg Pro Lys Phe Lys Glu Gly Arg 8085 agttatacga atgccagcaa ataaaagcag tttgattgcg aaaaaaaaaa aaaaaaaaaa 353gtactctgcg ttgttactcg agcttaaggg cgaattc 390 179 85 PRT Conus parius 179Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Met Trp Ile 1 5 1015 Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys Leu Ile Ile Arg Gly 20 2530 Leu Val Pro Asn Asp Leu Thr Pro Gln Arg Ile Leu Arg Ser Leu Ile 35 4045 Ser Gly Arg Thr Tyr Gly Ile Tyr Asp Ala Lys Pro Pro Phe Ser Cys 50 5560 Ala Gly Leu Arg Gly Gly Cys Val Leu Pro Pro Asn Leu Arg Pro Lys 65 7075 80 Phe Lys Glu Gly Arg 85 180 24 PRT Conus parius PEPTIDE (1)..(24)Xaa at residues 1, 2, 15, 16 and 20 may be Pro or hydroxy-Pro; Xaa atresidue 24 may be Glu or Gla 180 Xaa Xaa Phe Ser Cys Ala Gly Leu Arg GlyGly Cys Val Leu Xaa Xaa 1 5 10 15 Asn Leu Arg Xaa Lys Phe Lys Xaa 20 181489 DNA Conus planorbis CDS (21)..(251) 181 gaattcgccc ttatggatcc atgcag acg gcc tac tgg gtg atg atg atg atg 53 Met Gln Thr Ala Tyr Trp ValMet Met Met Met 1 5 10 atg gtg tgg att aca ggc cat ctg tct gaa ggt ggcaaa ttg aag gat 101 Met Val Trp Ile Thr Gly His Leu Ser Glu Gly Gly LysLeu Lys Asp 15 20 25 gca att agg ggt ttg gtg cca gac gac ttg acc tca atgttt gcg ttg 149 Ala Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Ser Met PheAla Leu 30 35 40 cat ctt ccg gtt tcc cat tct cgg tct agc agc aat ggt ctgaag aga 197 His Leu Pro Val Ser His Ser Arg Ser Ser Ser Asn Gly Leu LysArg 45 50 55 gct gac cta tgt atc cac aag att tgt cca cca cgg tat cac caaagc 245 Ala Asp Leu Cys Ile His Lys Ile Cys Pro Pro Arg Tyr His Gln Ser60 65 70 75 caa caa taaaagacgt cagacaacca ccacaacttt agtatgacatcgttaatagg 301 Gln Gln acttcagcaa gtattttaac atcactgtgg ttgtgatgaaatcagtcgcc ttaaaagatt 361 ggctttttcc ttgtttaaga gttgtacttg tatcagctttgcacttcgaa ataaagttga 421 tgtgatgaac caaaaaaaaa aaaaaaaaaa agtactctgcgttgttactc gagcttaagg 481 gcgaattc 489 182 77 PRT Conus planorbis 182Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Val Trp Ile Thr 1 5 1015 Gly His Leu Ser Glu Gly Gly Lys Leu Lys Asp Ala Ile Arg Gly Leu 20 2530 Val Pro Asp Asp Leu Thr Ser Met Phe Ala Leu His Leu Pro Val Ser 35 4045 His Ser Arg Ser Ser Ser Asn Gly Leu Lys Arg Ala Asp Leu Cys Ile 50 5560 His Lys Ile Cys Pro Pro Arg Tyr His Gln Ser Gln Gln 65 70 75 183 26PRT Conus planorbis PEPTIDE (1)..(26) Xaa at residues 18 and 19 may bePro or hydroxy-Pro; Xaa at residue 21 may be Tyr, 125I-Tyr,mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty 183 Ser Ser SerAsn Gly Leu Lys Arg Ala Asp Leu Cys Ile His Lys Ile 1 5 10 15 Cys XaaXaa Arg Xaa His Gln Ser Gln Gln 20 25 184 834 DNA Conus pulicarius CDS(1)..(246) misc_feature (1)..(834) n may be any nucleotide 184 atg cagacg gcc tac tgg gtg atg gtg atg atg atg atg gtg tgg gtt 48 Met Gln ThrAla Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 aca gcgcct gtg tct gaa ggt ggt aaa ttg agc gac gta att cgg ggt 96 Thr Ala ProVal Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 ttg gtg ccagac gac ata acc cca cag att att ttg caa agt ctg aat 144 Leu Val Pro AspAsp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 gcc agt cgt catgct tac aga cgt gtt cgt ctg aga gga cag ata tgt 192 Ala Ser Arg His AlaTyr Arg Arg Val Arg Leu Arg Gly Gln Ile Cys 50 55 60 atc tgg aag gta tgtcca cca cta cta caa tgg ata cat cca tta gta 240 Ile Trp Lys Val Cys ProPro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 aaa aga tgaatgacatcagacaaccg ccacaactgt agtacgacat cgttaacacg 296 Lys Arg acttcagcaaatattctaac atcacagtgg gttgtgaaga natcgggttg gctttaaaaa 356 aaanaatgggggnttttccc cntgggttta aaaaaanntn ggnnccgggn aannncccnn 416 nntnnnccccccccnntngg gagaaaaaaa aaannccnnt nnnggggggn nnncnaaaaa 476 aaaaaaaaaaaaaaaaaaaa aaaaancccc nggggggntg ntttnncccc ccnccccngg 536 gggggggggngntttnnccc cccccccgng gggggggggg nttttnnttt nngggggngc 596 cccccccccccccnnncnnn nnaanaannn nngggggggg ggaanaaaaa nannnnnnnn 656 nnnnnnnnnnttttntcnnt cnnccgngnn gnnaaaaaaa aaanttnatt tntnnannnc 716 nncnnnccnncnncnnaccc nnccccnncc ncnncanncn nagannanga ggggggggng 776 nnnnggngnannnnnannnn nnngaannng aggngngnnn cncgncnncg cncnngnc 834 185 82 PRTConus pulicarius misc_feature (1)..(834) n may be any nucleotide 185 MetGln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30Leu Val Pro Asp Asp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45Ala Ser Arg His Ala Tyr Arg Arg Val Arg Leu Arg Gly Gln Ile Cys 50 55 60Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 7580 Lys Arg 186 26 PRT Conus pulicarius PEPTIDE (1)..(26) Xaa at residues10 and 19 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 14,15 and 22 may be Pro or hydroxy-Pro 186 Val Arg Leu Arg Gly Gln Ile CysIle Xaa Lys Val Cys Xaa Xaa Leu 1 5 10 15 Leu Gln Xaa Ile His Xaa LeuVal Lys Arg 20 25 187 471 DNA Conus pulicarius CDS (1)..(246) 187 atgcag acg gcc tac tgg gtg atg gtg atg atg atg atg gtg tgg gtt 48 Met GlnThr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 acagcg cct gtg tct gaa ggt ggt aaa ttg agc gac gta att cgg ggt 96 Thr AlaPro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 ttg gtgcca gac gac tta acc cca cag att atc ttg caa agt ctg aat 144 Leu Val ProAsp Asp Leu Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 gcc agt cgtcat gct tac aga cgt gtt cgt ccg aga gga cag ata tgt 192 Ala Ser Arg HisAla Tyr Arg Arg Val Arg Pro Arg Gly Gln Ile Cys 50 55 60 atc tgg aag gtatgt cca cca cta cta caa tgg ata cat cca tta gta 240 Ile Trp Lys Val CysPro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 aaa agatgaatgacat cagacaaccg ccacaactgt agtacggcat cgttaacacg 296 Lys Argacttcagcaa atattttaac atcacagtgg ttgtgaagaa atcggttgct ttaaaaaaag 356attgggtttt tccttgttta agagttgtac tgatatcagt tctgcactat gaaataaagc 416tgatgtgacg aacaaaaaaa aaaaaaaaaa aaagtactct gcgttgttac tcgag 471 188 82PRT Conus pulicarius 188 Met Gln Thr Ala Tyr Trp Val Met Val Met Met MetMet Val Trp Val 1 5 10 15 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu SerAsp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Pro Gln Ile IleLeu Gln Ser Leu Asn 35 40 45 Ala Ser Arg His Ala Tyr Arg Arg Val Arg ProArg Gly Gln Ile Cys 50 55 60 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln TrpIle His Pro Leu Val 65 70 75 80 Lys Arg 189 26 PRT Conus pulicariusPEPTIDE (1)..(26) Xaa at residues 3, 14, 15 and 22 may be Pro orhydroxy-Pro; Xaa at residues 10 and 19 may be Trp (D or L) or bromo-Trp(D or L) 189 Val Arg Xaa Arg Gly Gln Ile Cys Ile Xaa Lys Val Cys Xaa XaaLeu 1 5 10 15 Leu Gln Xaa Ile His Xaa Leu Val Lys Arg 20 25 190 471 DNAConus pulicarius CDS (1)..(246) 190 atg cag acg gcc tac tgg gtg atg gtgatg atg atg atg gtg tgg gtt 48 Met Gln Thr Ala Tyr Trp Val Met Val MetMet Met Met Val Trp Val 1 5 10 15 aca gcg cct gtg tct gaa ggt ggt aaattg agc gac gta att cgg ggt 96 Thr Ala Pro Val Ser Glu Gly Gly Lys LeuSer Asp Val Ile Arg Gly 20 25 30 ttg gtg cca gac gac ata acc cca cag attatc ttg caa agt ctg aat 144 Leu Val Pro Asp Asp Ile Thr Pro Gln Ile IleLeu Gln Ser Leu Asn 35 40 45 gcc agt cgt cat gct tac aga cct gtt cgt ctgaga gga cag ata tgt 192 Ala Ser Arg His Ala Tyr Arg Pro Val Arg Leu ArgGly Gln Ile Cys 50 55 60 atc tgg aag gta tgt cca cca cta cta caa tgg atacat cca tta gta 240 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile HisPro Leu Val 65 70 75 80 aaa aga tgaatgacat cagacaaccg ccacaactgtagtacgacat cgttaacacg 296 Lys Arg acttcagcaa atattttaac atcacagtggttgtgaagaa atcggttgct ttaaaaaaag 356 attgggtttt tccttgttta agagttgtactgatatcagt tctgcactat gaaataaagc 416 tgatgtgacg aacaaaaaaa aaaaaaaaaaaaagtactct gcgttgttac tcgag 471 191 82 PRT Conus pulicarius 191 Met GlnThr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 ThrAla Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 LeuVal Pro Asp Asp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 AlaSer Arg His Ala Tyr Arg Pro Val Arg Leu Arg Gly Gln Ile Cys 50 55 60 IleTrp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80Lys Arg 192 27 PRT Conus pulicarius PEPTIDE (1)..(27) Xaa at residues 1,15, 16 and 23 may be Pro or hydroxy-Pro; Xaa at residues 11 and 20 maybe Trp (D or L) or bromo-Trp (D or L) 192 Xaa Val Arg Leu Arg Gly GlnIle Cys Ile Xaa Lys Val Cys Xaa Xaa 1 5 10 15 Leu Leu Gln Xaa Ile HisXaa Leu Val Lys Arg 20 25 193 375 DNA Conus rattus CDS (1)..(282) 193atg cag acg gcc tac tgg gtg atg gtg atg atg gtg gtg gtg ggg ttc 48 MetGln Thr Ala Tyr Trp Val Met Val Met Met Val Val Val Gly Phe 1 5 10 15acc gtc ggg ggt cac gtc cat caa tct cac agt cct aca tcg cgc agc 96 ThrVal Gly Gly His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 catggt gat gac tcc att cat gac aag acg att cat caa cat ctg ttt 144 His GlyAsp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 gcc cgtctt cct ctg gag aac aac gac gac cat cgt tct gtg gat ctt 192 Ala Arg LeuPro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 cct gca gggacc agc gca ggc gac atg aaa cca caa cgc caa aga cgt 240 Pro Ala Gly ThrSer Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Arg 65 70 75 80 ctc tgc tgcatc ttt gcc att ctt tgg ttc tgt tgt ctc ggt 282 Leu Cys Cys Ile Phe AlaIle Leu Trp Phe Cys Cys Leu Gly 85 90 taacagtaca aattgcaatg cactggccgattgaaagaac tgcaataaac ggaaaaaaaa 342 aaaaaaaaaa agtactctgc gttgttactcgag 375 194 94 PRT Conus rattus 194 Met Gln Thr Ala Tyr Trp Val Met ValMet Met Val Val Val Gly Phe 1 5 10 15 Thr Val Gly Gly His Val His GlnSer His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly Asp Asp Ser Ile His AspLys Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg Leu Pro Leu Glu Asn AsnAsp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala Gly Thr Ser Ala Gly AspMet Lys Pro Gln Arg Gln Arg Arg 65 70 75 80 Leu Cys Cys Ile Phe Ala IleLeu Trp Phe Cys Cys Leu Gly 85 90 195 13 PRT Conus rattus PEPTIDE(1)..(13) Xaa at residue 9 may be Trp (D or L) or bromo-Trp (D or L 195Leu Cys Cys Ile Phe Ala Ile Leu Xaa Phe Cys Cys Leu 1 5 10 196 494 DNAConus striatus CDS (21)..(287) 196 gaattcgccc ttatggatcc atg cag acg gcctac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val MetMet 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aacgac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp15 20 25 gta att cgg ggt ttg gtg cca cac atc tta acc cca cag cat atc ttg149 Val Ile Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His Ile Leu 3035 40 caa agt ctg att tcc cct ctt cgt tct aac aac ggt cgt tcg agt gga197 Gln Ser Leu Ile Ser Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly 4550 55 gca caa ata tgc atc tgg aag gta tgt cca cca tcc cca tgg aga caa245 Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Gln 6065 70 75 cca caa gaa atg atg aat gac atc aga caa ccg cca caa ctg 287 ProGln Glu Met Met Asn Asp Ile Arg Gln Pro Pro Gln Leu 80 85 tagtacgacatcgttgatac gactttagca aatattttaa catcactgtg gttgtgaaga 347 aatcagttgctttaaaagat tggatttttc cttgtttaag agttgtactg atatcagctc 407 tgcactatgaaataaagctg atgtgacaaa caaaaaaaaa aaaaaaaaaa gtactctgcg 467 ttgttactcgagcttaaggg cgaattc 494 197 89 PRT Conus striatus 197 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu SerGlu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His IleLeu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg SerAsn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val CysPro Pro Ser Pro Trp Arg Gln Pro Gln Glu Met Met 65 70 75 80 Asn Asp IleArg Gln Pro Pro Gln Leu 85 198 38 PRT Conus striatus PEPTIDE (1)..(38)Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaaat residues 18, 19, 21, 25, 35 and 36 may be Pro or hydroxy-Pro; Xaa atresidue 27 may be Glu or Gla 198 Ser Asn Asn Gly Arg Ser Ser Gly Ala GlnIle Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Gln XaaGln Xaa Met Met Asn Asp Ile 20 25 30 Arg Gln Xaa Xaa Gln Leu 35 199 412DNA Conus striolatus CDS (1)..(240) 199 atg cag acg gcc tac tgg gtg atggtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met ValMet Met Met Val Trp Ile Thr 1 5 10 15 gac cct ctg tct gaa ggt ggt aaattg aac gac gta att cgg ggt ttg 96 Asp Pro Leu Ser Glu Gly Gly Lys LeuAsn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cgc atc tta acc cca cag catacc ttg cga agt ccg act tcc 144 Val Pro Arg Ile Leu Thr Pro Gln His ThrLeu Arg Ser Pro Thr Ser 35 40 45 ctt ctt cgt tct aac acc ggt ggt tcg agtgga gca caa ata tgc atc 192 Leu Leu Arg Ser Asn Thr Gly Gly Ser Ser GlyAla Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca tcc cca tgg aga cgatca caa gga aaa aga 240 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg SerGln Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaagcg ccacaactgt agtacgacatcgttgatacg acttcagcaa 300 gtattttaac atcactgtgg ttgtgaagaa atcagttgctttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gccctgtgaaataaagctga tg 412 200 80 PRT Conus striolatus 200 Met Gln Thr Ala TyrTrp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Asp Pro Leu SerGlu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Arg IleLeu Thr Pro Gln His Thr Leu Arg Ser Pro Thr Ser 35 40 45 Leu Leu Arg SerAsn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val CysPro Pro Ser Pro Trp Arg Arg Ser Gln Gly Lys Arg 65 70 75 80 201 26 PRTConus striolatus PEPTIDE (1)..(26) Xaa at residues 14 and 22 may be Trp(D or L) or bromo-Trp (D or L); Xaa at residues 18, 19 and 21 may be Proor hydroxy-Pro 201 Ser Asn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys IleXaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Arg Ser Gln 20 25 202412 DNA Conus striolatus CDS (1)..(240) 202 atg cag acg gcc tac tgg gtgatg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val MetVal Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggtaaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly LysLeu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cagcat atc ttg caa agt ctg att tcc 144 Val Pro His Ile Leu Thr Pro Gln HisIle Leu Gln Ser Leu Ile Ser 35 40 45 cct ctt cgt tct aac aac ggt cgt tcgagt gga gca caa ata tgc atc 192 Pro Leu Arg Ser Asn Asn Gly Arg Ser SerGly Ala Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca tcc cca tgg agacga tca caa gga aaa aga 240 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg ArgSer Gln Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaagcg ccacaactgtagtacgacat cgttgatacg acttcagcaa 300 gtattttaac atcactgtgg ttgtgaagaaatcagttgct ttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctctgcactgtgaa ataaagctga tg 412 203 80 PRT Conus striolatus 203 Met Gln ThrAla Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala ProLeu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val ProHis Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro LeuArg Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp LysVal Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln Gly Lys Arg 65 70 75 80 20426 PRT Conus striolatus PEPTIDE (1)..(26) Xaa at residues 14 and 22 maybe Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19 and 21 maybe Pro or hydroxy-Pro 204 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln IleCys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Arg Ser Gln 2025 205 497 DNA Conus striolatus CDS (21)..(257) 205 gaattcgcccttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln ThrAla Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aaa gac cct ctgtct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Lys Asp Pro Leu SerGlu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac atctta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Ile LeuThr Pro Gln His Ile Leu 30 35 40 caa agt ctg att tcc cct ctt cgt tct aacaac ggt cgt tcg agt gga 197 Gln Ser Leu Ile Ser Pro Leu Arg Ser Asn AsnGly Arg Ser Ser Gly 45 50 55 gca caa ata tgc aac tgg aag gta tgt cca ccatcc cca tgg aga cga 245 Ala Gln Ile Cys Asn Trp Lys Val Cys Pro Pro SerPro Trp Arg Arg 60 65 70 75 cca cga gga aaa tgatgaatga catcagacaaccgccacaac tgtagtacga 297 Pro Arg Gly Lys cttcgttgat acgactttagcaaatatttt aacatcactg tggttgtgaa gaaatcagtt 357 gctttaaaag attggatttttccttgttta agagttgtac tgatatcagc tctgcactat 417 gaaataaagc tgatgtgacaaacaaaaaaa aaaaaaaaaa aaagtactct gcgttgttac 477 tcgagcttaa gggcgaattc497 206 79 PRT Conus striolatus 206 Met Gln Thr Ala Tyr Trp Val Met ValMet Met Met Val Trp Ile Lys 1 5 10 15 Asp Pro Leu Ser Glu Gly Gly LysLeu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro GlnHis Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg Ser Asn Asn Gly ArgSer Ser Gly Ala Gln Ile Cys Asn 50 55 60 Trp Lys Val Cys Pro Pro Ser ProTrp Arg Arg Pro Arg Gly Lys 65 70 75 207 26 PRT Conus striolatus PEPTIDE(1)..(26) Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (Dor L); Xaa at residues 18, 19, 21 and 25 may be Pro or hydroxy-Pro 207Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Asn Xaa Lys Val 1 5 1015 Cys Xaa Xaa Ser Xaa Xaa Arg Arg Xaa Arg 20 25 208 496 DNA Conusstriolatus CDS (21)..(287) 208 gaattcgccc ttatggatcc atg cag acg gcc tactgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 15 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25gta att cgg ggt ttg gtg cca cac atc tta acc cca cag cat atc ttg 149 ValIle Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His Ile Leu 30 35 40 caaagt ctg att tcc cct ctt cgt tct aac aac ggt cgt tcg agt gga 197 Gln SerLeu Ile Ser Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly 45 50 55 gca caaata tgc atc tgg aag gta tgt cca cca tcc cca tgg aga caa 245 Ala Gln IleCys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Gln 60 65 70 75 cca caagaa atg atg aat gac atc aga caa ccg cca caa ctg 287 Pro Gln Glu Met MetAsn Asp Ile Arg Gln Pro Pro Gln Leu 80 85 tagtacgaca tcgttgatacgactttagca aatattttaa catcactgtg gttgtgaaga 347 aatcagttgc tttaaaagattggatttttc cttgtttaag agttgtactg atatcagctc 407 tgcactatga aataaagctgatgtgacaaa cgaaaaaaaa aaaaaaaaaa aagtactctg 467 cgttgttact cgagcttaagggcgaattc 496 209 89 PRT Conus striolatus 209 Met Gln Thr Ala Tyr TrpVal Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser GluGly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile LeuThr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg Ser AsnAsn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys ProPro Ser Pro Trp Arg Gln Pro Gln Glu Met Met 65 70 75 80 Asn Asp Ile ArgGln Pro Pro Gln Leu 85 210 38 PRT Conus striolatus PEPTIDE (1)..(38) Xaaat residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa atresidues 18, 19, 21, 25, 35 and 36 may be Pro or hydroxy-Pro; Xaa atresidue 27 may be Glu or Gla 210 Ser Asn Asn Gly Arg Ser Ser Gly Ala GlnIle Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Gln XaaGln Xaa Met Met Asn Asp Ile 20 25 30 Arg Gln Xaa Xaa Gln Leu 35 211 413DNA Conus sulcatus CDS (1)..(234) 211 atg cag acg gcc tac tgg gtg atggtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met ValMet Met Met Val Trp Ile Thr 1 5 10 15 gcc tct ctg tct gaa ggt ggt aaaccg aac gac gtc att cgg ggt ttt 96 Ala Ser Leu Ser Glu Gly Gly Lys ProAsn Asp Val Ile Arg Gly Phe 20 25 30 gtg cca gac gac tta acc cca cag cttatc ttg cga agt ctg att tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu IleLeu Arg Ser Leu Ile Ser 35 40 45 cgt cgt cgt tct gac aag gat gtt ggg aagaga atg gaa tgt tac tgg 192 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys ArgMet Glu Cys Tyr Trp 50 55 60 aag gca tgt aga ccc acg cta tcg aga cga catgat ctt ggg 234 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu Gly65 70 75 taaaagatga atgacgtcag acaacagcca caactatagt atgacatcgttaatacgact 294 tcagcaaata ttttaacatc actgtggttg tgaagaaatc agttgctttaaaagattgga 354 tttttccgtg tttaagagtt gtactgatat cagctctgcc ctgtgaaataaagctgatg 413 212 78 PRT Conus sulcatus 212 Met Gln Thr Ala Tyr Trp ValMet Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Ser Leu Ser Glu GlyGly Lys Pro Asn Asp Val Ile Arg Gly Phe 20 25 30 Val Pro Asp Asp Leu ThrPro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp LysAsp Val Gly Lys Arg Met Glu Cys Tyr Trp 50 55 60 Lys Ala Cys Arg Pro ThrLeu Ser Arg Arg His Asp Leu Gly 65 70 75 213 27 PRT Conus sulcatusPEPTIDE (1)..(27) Xaa at residue 11 may be Glu or Gla; Xaa at residue 13may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr orO-phospho-Tyr; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D orL); Xaa at residue 19 may be Pro or hydroxy-Pro 213 Arg Ser Asp Lys AspVal Gly Lys Arg Met Xaa Cys Xaa Xaa Lys Ala 1 5 10 15 Cys Arg Xaa ThrLeu Ser Arg Arg His Asp Leu 20 25 214 472 DNA Conus terebra CDS(1)..(234) 214 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tggatt aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp IleThr 1 5 10 15 gcc cct ctg tct gaa ggt gat aaa ttg aac gac gta att cggggt ttg 96 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg GlyLeu 20 25 30 gtg cca gat aac tta gcc cca cag ctt gtt ttg caa agt ctg gattcc 144 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu Gln Ser Leu Asp Ser35 40 45 cgt cgt cat cct cac ggc att cgt cag gat gga gcc caa ata tgt atc192 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 5055 60 tgg aag ata tgt cca cca tcc cca tgg aaa cga ctt gga tct 234 TrpLys Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu Gly Ser 65 70 75 taagaaaagaaacaattgac gtcagacaac cgccacaact tgagtacgac atcgttaata 294 caacttcagcaaatatgaaa ttttcagcat cactgtggtt gtgaagaaat cagttgcttt 354 aaaagattggatttgtcctt gtttaagagt tgtactgatg tcatctctgc actgtgaaat 414 aaagctgatgtgacaaacaa aaaaaaaaaa aaaaaagtac tctgcgttgt tactcgag 472 215 78 PRTConus terebra 215 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp ValIle Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu GlnSer Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly AlaGln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg LeuGly Ser 65 70 75 216 28 PRT Conus terebra PEPTIDE (1)..(28) Xaa atresidues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15and 23 may be Trp (D or L) or bromo-Trp (D or L) 216 His Xaa His Gly IleArg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa XaaSer Xaa Xaa Lys Arg Leu Gly Ser 20 25 217 474 DNA Conus terebra CDS(1)..(234) 217 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tggatt aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp IleThr 1 5 10 15 gcc cct ctg tct gaa ggt gat aaa ttg aac gac gta att cggggt ttg 96 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg GlyLeu 20 25 30 gtg cca gat aac tta gcc cca cag ctt gtt ttg cat agt ctg gattcc 144 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu His Ser Leu Asp Ser35 40 45 cgt cgt cat cct cac ggc att cgt cag gat gga gcc caa ata tgt atc192 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 5055 60 tgg aag ata tgt cca cca tcc cca tgg aga cga ctt gga tct 234 TrpLys Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 65 70 75 taagaaaagaaacaattgac gtcagacaac cgccacatct tgagtacgac atcgttaata 294 cgacttcagcaaatatgaaa ttttcagcat cactgtggtt gtgaagaaat cagttgcctt 354 aaaagattggatttgtcctt gtttaagagt tgtactgatg tcatctctgc actatgaaat 414 aaagctgatgtgacaaacaa aaaaaaaaaa aaaaaaaagt actctgcgtt gttactcgag 474 218 78 PRTConus terebra 218 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp ValIle Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu HisSer Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly AlaGln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Arg Arg LeuGly Ser 65 70 75 219 28 PRT Conus terebra PEPTIDE (1)..(28) Xaa atresidues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15and 23 may be Trp (D or L) or bromo-Trp (D or L) 219 His Xaa His Gly IleArg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa XaaSer Xaa Xaa Arg Arg Leu Gly Ser 20 25 220 485 DNA Conus vexillum CDS(21)..(236) 220 gaattcgccc ttatggatcc atg cag atg gcc tac tgg gtg atggtg atg atg 53 Met Gln Met Ala Tyr Trp Val Met Val Met Met 1 5 10 atggtg tgg att aaa ggc cct gtg tcc gaa ggt ggt aaa ttg aac gac 101 Met ValTrp Ile Lys Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta attcgg ggt ttg gtg cca gac gac ttg acc cca gtg tct gcc ttg 149 Val Ile ArgGly Leu Val Pro Asp Asp Leu Thr Pro Val Ser Ala Leu 30 35 40 cat cat ccggtt tcc cat cgt cgg tct cac agc agt agt ttg tgg tgt 197 His His Pro ValSer His Arg Arg Ser His Ser Ser Ser Leu Trp Cys 45 50 55 gta tgt cca ttcagg gtg tgt cca cca tgc cat gga aga tgacctggtc 246 Val Cys Pro Phe ArgVal Cys Pro Pro Cys His Gly Arg 60 65 70 ccaaaccaac aaaataacgtcagacaaccg ccacaacttt agtacgacat cccttaatac 306 gacttcagca agtattttaacatcactatg gtgtgatgaa atcagttgct ttaaaagatt 366 ggatttttcc ttgtttaagagttgcactga taacagccca gcagtatgaa ataaagttga 426 tgtggcaaaa aaaaaaaaaaaagtactctg cgttgttact cgagcttaag ggcgaattc 485 221 72 PRT Conus vexillum221 Met Gln Met Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Lys 1 510 15 Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 2025 30 Val Pro Asp Asp Leu Thr Pro Val Ser Ala Leu His His Pro Val Ser 3540 45 His Arg Arg Ser His Ser Ser Ser Leu Trp Cys Val Cys Pro Phe Arg 5055 60 Val Cys Pro Pro Cys His Gly Arg 65 70 222 19 PRT Conus vexillumPEPTIDE (1)..(19) Xaa at residue 7 may be Trp (D or L) or bromo-Trp (Dor L); Xaa at residues 11, 16 and 17 may be Pro or hydroxy-Pro 222 SerHis Ser Ser Ser Leu Xaa Cys Val Cys Xaa Phe Arg Val Cys Xaa 1 5 10 15Xaa Cys His 223 481 DNA Conus vexillum CDS (21)..(257) 223 gaattcgcccttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln ThrAla Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ttgtct gaa ggt ggt aaa ctg aac gat 101 Met Val Trp Ile Thr Ala Pro Leu SerGlu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttc gcg cta gat gactta gcc caa agc cgt att atg 149 Val Ile Arg Gly Phe Ala Leu Asp Asp LeuAla Gln Ser Arg Ile Met 30 35 40 caa agt ctg gtt ttc agt cat cag cct cttcca acg gca tcc ata tgt 197 Gln Ser Leu Val Phe Ser His Gln Pro Leu ProThr Ala Ser Ile Cys 45 50 55 atc tgg aag ata tgt cca cca gac cca tgg agacga cat gat ctt cag 245 Ile Trp Lys Ile Cys Pro Pro Asp Pro Trp Arg ArgHis Asp Leu Gln 60 65 70 75 aaa agt aac aaa tgacgtcaga caaccgccacaacttgaata caacatcatt 297 Lys Ser Asn Lys aatacgactt cagcaaatattttagcatca ctgtgattgt tcggaagtca gttgctttaa 357 aagattggat ttgtccctgttgtattgatg tcaactctgc actatgaaat aaagctgatg 417 tgacaagcaa aaaaaaaaaaaaaaaaagta ctctgcgttg ttactcgagc ttaagggcga 477 attc 481 224 79 PRTConus vexillum 224 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met ValTrp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp ValIle Arg Gly Phe 20 25 30 Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met GlnSer Leu Val Phe 35 40 45 Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys IleTrp Lys Ile Cys 50 55 60 Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln LysSer Asn Lys 65 70 75 225 38 PRT Conus vexillum PEPTIDE (1)..(38) Xaa atresidues 11, 14, 24, 25 and 27 may be Pro or hydroxy-Pro; Xaa atresidues 20 and 28 may be Trp (D or L) or bromo-Trp (D or L) 225 Ile MetGln Ser Leu Val Phe Ser His Gln Xaa Leu Xaa Thr Ala Ser 1 5 10 15 IleCys Ile Xaa Lys Ile Cys Xaa Xaa Asp Xaa Xaa Arg Arg His Asp 20 25 30 LeuGln Lys Ser Asn Lys 35 226 384 DNA Conus vexillum CDS (1)..(285) 226 atgcag acg gcc tac tgg gtg atg gtg atg atg atg gtg gtg ggg ttc 48 Met GlnThr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 accgtc gag agt cac gtc cat cag tct cac agt cct aca tcg cgc agc 96 Thr ValGlu Ser His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 cat ggtgat gac tcc att cat gac aag acg att cat caa cat ctg ttt 144 His Gly AspAsp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 gcc cgt cttcct ctg gag aac aac gac gac cat cgt tct gtg gat ctt 192 Ala Arg Leu ProLeu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 cct gca ggg actagc gca ggc gac atg aaa cca caa cgc cag aaa cgt 240 Pro Ala Gly Thr SerAla Gly Asp Met Lys Pro Gln Arg Gln Lys Arg 65 70 75 80 ttc tgc tgc atcttt gcc ccg att ctt ttg ttc tgt tgt ttc ggt 285 Phe Cys Cys Ile Phe AlaPro Ile Leu Leu Phe Cys Cys Phe Gly 85 90 95 taacagcaca aattacactgcactggccga ttgaaagaac tgcaataaac ggtaaagcaa 345 aaaaaaaaaa aaaaaaagtactctgcgttg ttactcgag 384 227 95 PRT Conus vexillum 227 Met Gln Thr AlaTyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 Thr Val GluSer His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly AspAsp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg LeuPro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala GlyThr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Lys Arg 65 70 75 80 Phe CysCys Ile Phe Ala Pro Ile Leu Leu Phe Cys Cys Phe Gly 85 90 95 228 14 PRTConus vexillum PEPTIDE (1)..(14) Xaa at residue 7 may be Pro orhydroxy-Pro 228 Phe Cys Cys Ile Phe Ala Xaa Ile Leu Leu Phe Cys Cys Phe1 5 10 229 40 PRT Conus tulipa 229 Glx Thr Asp Val Leu Leu Glu Ala ThrLeu Leu Thr Thr Pro Ala Pro 1 5 10 15 Glu Gln Arg Leu Phe Cys Phe TrpLys Ser Cys Trp Pro Arg Pro Tyr 20 25 30 Pro Trp Arg Arg Arg Asp Leu Asn35 40 230 40 PRT Conus magus 230 Glx Thr Asp Val Leu Leu Asp Ala Thr LeuLeu Thr Thr Pro Ala Pro 1 5 10 15 Glu Gln Arg Leu Phe Cys Phe Trp LysSer Cys Trp Pro Arg Pro Tyr 20 25 30 Pro Trp Arg Arg Arg Asn Leu Asn 3540 231 40 PRT Conus geographus 231 Glx Thr Asp Val Leu Leu Glu Ala ThrLeu Leu Thr Thr Pro Ala Pro 1 5 10 15 Glu Gln Arg Leu Phe Cys Phe TrpLys Ser Cys Thr Trp Arg Pro Tyr 20 25 30 Pro Trp Arg Arg Arg Asp Leu Asn35 40 232 21 PRT Conus tulipa 232 Leu Phe Cys Phe Trp Lys Ser Cys TrpPro Arg Pro Tyr Pro Trp Arg 1 5 10 15 Arg Arg Asp Leu Asn 20 233 21 PRTConus magus 233 Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg Pro Tyr ProTrp Arg 1 5 10 15 Arg Arg Asn Leu Asn 20 234 21 PRT Conus geographus 234Leu Phe Cys Phe Trp Lys Ser Cys Thr Trp Arg Pro Tyr Pro Trp Arg 1 5 1015 Arg Arg Asp Leu Asn 20 235 19 PRT Conus generalis 235 Ser His Ser SerSer Leu Trp Cys Val Cys Pro Phe Arg Val Cys Pro 1 5 10 15 Pro Cys His236 19 PRT Conus vexillum 236 Ser His Ser Ser Ser Leu Trp Cys Val CysPro Phe Arg Val Cys Pro 1 5 10 15 Pro Cys His 237 33 PRT Conus flavidus237 His Asp His Gly Ile Arg Pro Lys Arg Val Asp Ile Cys Asn Trp Arg 1 510 15 Ile Cys Ala Pro Asn Pro Leu Arg Arg His Asp Leu Lys Lys Gly Asn 2025 30 Asn 238 33 PRT Conus emaciatus 238 His Thr His Gly Ile Arg Pro LysGly Asp Gly Ile Cys Ile Trp Lys 1 5 10 15 Val Cys Pro Pro Asp Pro TrpArg Arg His Arg Leu Lys Lys Arg Asn 20 25 30 Asn 239 33 PRT Conusaurisiacus 239 His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys IleTrp Lys 1 5 10 15 Val Cys Pro Pro Asp Pro Trp Arg Arg His His Leu LysLys Arg Asn 20 25 30 Asn 240 28 PRT Conus terebra 240 His Pro His GlyIle Arg Gln Asp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Ile Cys ProPro Ser Pro Trp Lys Arg Leu Gly Ser 20 25 241 28 PRT Conus terebra 241His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 1015 Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 20 25 242 28 PRTConus litoglyphus 242 His Pro His Gly Ile Arg Gln Asp Gly Ala Gln IleCys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu GlySer 20 25 243 28 PRT Conus litoglyphus 243 His Pro His Gly Ile Arg GlnAsp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Ser ProTrp Arg Arg Leu Gly Ser 20 25 244 23 PRT Conus consors 244 Asp Arg SerAsp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys ValCys Pro Pro Ser Pro 20 245 25 PRT Conus consors 245 Asp Arg Ser Asp AsnGly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys ProPro Ser Pro Trp Lys 20 25 246 28 PRT Conus consors 246 Ala Arg Ser AspAsn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val CysPro Pro Ser Pro Trp Arg Arg Pro Gln 20 25 247 26 PRT Conus striolatus247 Ser Asn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp Lys Val 1 510 15 Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln 20 25 248 26 PRT Conusstriolatus 248 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Asn TrpLys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Arg Pro Arg 20 25 249 26PRT Conus striolatus 249 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile CysIle Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln 20 25250 38 PRT Conus striolatus 250 Ser Asn Asn Gly Arg Ser Ser Gly Ala GlnIle Cys Ile Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Gln ProGln Glu Met Met Asn Asp Ile 20 25 30 Arg Gln Pro Pro Gln Leu 35 251 38PRT Conus striatus 251 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile CysIle Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Gln Pro Gln GluMet Met Asn Asp Ile 20 25 30 Arg Gln Pro Pro Gln Leu 35 252 25 PRT Conusaurisiacus 252 Leu His Ser Asp Ser Ser Asp Gln Lys Gly Ala Gln Ile CysIle Trp 1 5 10 15 Lys Val Cys Pro Pro Pro Pro Trp Arg 20 25 253 34 PRTConus aurisiacus 253 Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met AsnAla Trp Thr 1 5 10 15 Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val CysPro Pro Pro Pro 20 25 30 Trp Arg 254 37 PRT Conus aurisiacus 254 Leu ArgSer Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Ser Thr 1 5 10 15 GlyAla Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser Pro 20 25 30 TrpArg Arg Thr Gln 35 255 28 PRT Conus circumcisus 255 Leu Arg Ser Asp SerSer Gly Gln Lys Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys ProLeu Ser Pro Trp Arg Arg Pro Gln 20 25 256 32 PRT Conus circumcisus 256Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile Trp 1 5 1015 Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln Gly Lys Asp Glu 20 2530 257 28 PRT Conus achatinus 257 Leu Arg Ser Asp Asn Gly Gly Ser SerGly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro TrpArg Arg Pro Gln 20 25 258 22 PRT Conus stercusmuscarum 258 Leu Gly IleGly Ser Ser Asp Gln Asn Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Val CysPro Pro Ser Pro 20 259 25 PRT Conus consors 259 Asn Gly Ser Gly Ser SerAsn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys Pro ProSer Pro Trp Arg 20 25 260 25 PRT Conus consors 260 Asn Gly Ser Gly SerSer Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys ProPro Thr Pro Trp Arg 20 25 261 25 PRT Conus magus 261 Asn Gly Ser Gly SerSer Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys ProPro Ser Pro Trp Arg 20 25 262 25 PRT Conus nobilis 262 Asn Gly Ser GlySer Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val CysPro Pro Thr Pro Trp Arg 20 25 263 27 PRT Conus sulcatus 263 Arg Ser AspLys Asp Val Gly Lys Arg Met Glu Cys Tyr Trp Lys Ala 1 5 10 15 Cys ArgPro Thr Leu Ser Arg Arg His Asp Leu 20 25 264 40 PRT Conus bocki 264 ArgSer Asp Lys Asp Asp Pro Gly Gly Gln Glu Cys Tyr Trp Asn Val 1 5 10 15Cys Ala Pro Asn Gln Gly Asp His Met Ile Leu Arg Lys Lys Met Asn 20 25 30Asp Asp Arg Gln Pro Pro Gln Leu 35 40 265 19 PRT Conus betulinus 265 ArgSer Asp Ser Asp Val Arg Glu Val Pro Val Cys Ser Trp Lys Ile 1 5 10 15Cys Pro Pro 266 22 PRT Conus loroisii 266 Arg Ser Asp Ser Asp Val ArgGlu Val Tyr Ile Leu Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Leu Pro 20267 32 PRT Conus gladiator 267 His Pro Ala Asn Val Arg Gln Gln Gly LysIle Cys Val Trp Lys Val 1 5 10 15 Cys Pro Pro Trp Pro Val Arg Ser ProGly Pro Gln Pro Lys Asn Lys 20 25 30 268 32 PRT Conus gladiator 268 HisPro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp Lys Val 1 5 10 15Cys Pro Pro Ser Pro Val Arg Ser Pro Gly Pro Leu Pro Lys Asn Lys 20 25 30269 41 PRT Conus musicus 269 Gly Met Gly Pro Gly Asp Leu Ser Leu Gln LysMet Phe Pro Ser Leu 1 5 10 15 Ala Leu Gly Pro Gly Gly Asp Val Ile CysArg Trp Lys Val Cys Pro 20 25 30 Pro Thr Pro Trp Lys Arg Leu Ile Lys 3540 270 49 PRT Conus musicus 270 Gly Met Val Pro Gly Asp Leu Ala Leu GlnTyr Leu Phe Pro Ser Leu 1 5 10 15 Ala Phe Asn Pro Pro Asp Ile Cys ThrTrp Lys Val Cys Pro Pro Pro 20 25 30 Pro Trp Arg Arg Pro Lys Lys Ile ThrAsp Val Gly Gln Pro Pro Gln 35 40 45 Leu 271 49 PRT Conus musicus 271Gly Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu 1 5 1015 Ala Phe Ser Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 20 2530 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln 35 4045 Leu 272 49 PRT Conus musicus 272 Gly Met Val Pro Gly Asp Leu Val LeuGln Tyr Leu Phe Pro Ser Leu 1 5 10 15 Ala Phe Asn Pro Pro Asp Ile CysThr Trp Lys Val Cys Pro Pro Pro 20 25 30 Pro Trp Arg Arg Pro Lys Lys IleThr Asp Val Arg Gln Pro Pro Gln 35 40 45 Leu 273 29 PRT Conus miles 273Glx Gln Asp Gln Ser Pro His His Val Cys Cys Ala Ile Gly Pro Val 1 5 1015 Leu Pro Phe Cys Cys Val Ser Trp Leu His Lys Leu His 20 25 274 14 PRTConus miles 274 Leu Cys Cys Ile Phe Ala Pro Ile Leu Trp Phe Cys Cys His1 5 10 275 13 PRT Conus rattus 275 Leu Cys Cys Ile Phe Ala Ile Leu TrpPhe Cys Cys Leu 1 5 10 276 15 PRT Conus capitaneus 276 Gly Phe Cys CysAsp Phe Pro Pro Ile Phe Trp Phe Cys Cys Ile 1 5 10 15 277 25 PRT Conusmiles 277 Glx Gly Phe Cys Cys Val Val Ile Pro Ile Leu Trp Phe Cys CysGly 1 5 10 15 Gly Tyr Arg Thr Asn Gly Thr Ala Asp 20 25 278 14 PRT Conusvexillum 278 Phe Cys Cys Ile Phe Ala Pro Ile Leu Leu Phe Cys Cys Phe 1 510 279 45 PRT Conus sulcatus 279 Glx Ser Gly Cys Arg Val Pro Phe Glu LeuLys Cys Ile Trp Lys Phe 1 5 10 15 Cys Thr Ile Tyr Pro Ser Arg Pro PheAla Ser Leu Glu Glu Lys Asp 20 25 30 Glu Cys Gln Thr Val Thr Ile Thr ValThr Trp Asp Phe 35 40 45 280 45 PRT Conus cinereus 280 Ser Ser Gly CysSer Val Ser Leu Gly Phe Lys Cys Phe Trp Lys Ser 1 5 10 15 Cys Thr ValIle Pro Val Arg Pro Phe Val Ser Leu Glu Glu Glu Asn 20 25 30 Glu Cys GlnLys Val Gln Ile Ser Ala Val Trp Gly Pro 35 40 45 281 25 PRT Conus parius281 Pro Pro Phe Ser Cys Ser Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 1 510 15 Asn Leu Arg Pro Lys Phe Asn Lys Gly 20 25 282 24 PRT Conus parius282 Pro Pro Phe Ser Cys Ala Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 1 510 15 Asn Leu Arg Pro Lys Phe Lys Glu 20 283 29 PRT Conus wittigi 283Ser Ser Asp Gly Ser Asp Pro Lys Ala Lys Lys Gln Cys Met Trp Lys 1 5 1015 Arg Cys Ile Pro Asp Gln Ser Arg Leu Glu Glu Asp Glu 20 25 284 30 PRTConus cinereus 284 Ser Ser Asp Gly Lys Ala Lys Lys Gln Cys Ala Trp LysThr Cys Val 1 5 10 15 Pro Thr Gln Trp Arg Arg Arg Asp Leu Lys Glu LysAsp Glu 20 25 30 285 30 PRT Conus cinereus 285 Ser Ser Asp Gly Lys AlaLys Arg Asn Cys Phe Trp Lys Ala Cys Val 1 5 10 15 Pro Glu Gln Trp ArgGln Arg Asp Pro Lys Glu Lys Asp Glu 20 25 30 286 30 PRT Conus cinereus286 Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Trp Lys Ala Cys Val 1 510 15 Pro Glu Gln Trp Arg Gln Arg Asp Leu Lys Glu Lys Asp Glu 20 25 30287 37 PRT Conus nobilis 287 Phe Arg Pro Ala Val Lys Ser Arg Ser Arg ArgAla Pro Pro Cys Val 1 5 10 15 Trp Lys Val Cys Pro Ala Pro Pro Trp LeuVal Thr Lys Arg Lys Gln 20 25 30 Glu Thr Ser Asp Tyr 35 288 37 PRT Conusnobilis 288 Phe Arg Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro CysVal 1 5 10 15 Trp Lys Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys ArgLys Gln 20 25 30 Glu Thr Ser Asp Tyr 35 289 37 PRT Conus miles 289 PheArg Pro Ala Met Gln Ser Arg Ser Gly Gly Met Ser Leu Cys Leu 1 5 10 15Trp Lys Val Cys Pro Ala Ala Pro Trp Leu Val Ala Lys Arg Lys Gln 20 25 30Glu Thr Ser Asp Tyr 35 290 21 PRT Conus tulipa 290 His Phe Asn Ser ValVal Pro Thr Val Tyr Ile Cys Met Trp Lys Val 1 5 10 15 Cys Pro Pro SerPro 20 291 21 PRT Conus purpurascens 291 Glx Ser Glu Glu Glu Lys Ile CysLeu Trp Lys Ile Cys Pro Pro Pro 1 5 10 15 Pro Trp Arg Arg Ser 20 292 21PRT Conus purpurascens 292 Glu Ser Asn Gly Val Glu Ile Cys Met Trp LysVal Cys Pro Pro Ser 1 5 10 15 Pro Trp Arg Arg Ser 20 293 38 PRT Conusvexillum 293 Ile Met Gln Ser Leu Val Phe Ser His Gln Pro Leu Pro Thr AlaSer 1 5 10 15 Ile Cys Ile Trp Lys Ile Cys Pro Pro Asp Pro Trp Arg ArgHis Asp 20 25 30 Leu Gln Lys Ser Asn Lys 35 294 38 PRT Conus muriculatus294 Ile Met Gln Ser Leu Val Phe Ser His Gln Pro Leu Pro Thr Ala Ser 1 510 15 Ile Cys Ile Trp Lys Ile Cys Pro Pro Asp Pro Trp Arg Arg His Asp 2025 30 Leu Gln Lys Ser Asn Lys 35 295 26 PRT Conus pulicarius 295 Val ArgLeu Arg Gly Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Leu 1 5 10 15 LeuGln Trp Ile His Pro Leu Val Lys Arg 20 25 296 26 PRT Conus pulicarius296 Val Arg Pro Arg Gly Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Leu 1 510 15 Leu Gln Trp Ile His Pro Leu Val Lys Arg 20 25 297 27 PRT Conuspulicarius 297 Pro Val Arg Leu Arg Gly Gln Ile Cys Ile Trp Lys Val CysPro Pro 1 5 10 15 Leu Leu Gln Trp Ile His Pro Leu Val Lys Arg 20 25 29830 PRT Conus mustelinus 298 Leu Val Ser His Thr Ser Ser Lys Tyr Pro GlyVal Thr Phe Cys Pro 1 5 10 15 Trp Lys Val Cys Pro Pro Ala Pro Trp ArgIle Leu Gly Val 20 25 30 299 22 PRT Conus baileyi 299 His Ser Asp SerIle Ile Leu Arg Gly Leu Cys Ile Trp Lys Val Cys 1 5 10 15 Glu Pro ProPro Gln Arg 20 300 26 PRT Conus planorbis 300 Ser Ser Ser Asn Gly LeuLys Arg Ala Asp Leu Cys Ile His Lys Ile 1 5 10 15 Cys Pro Pro Arg TyrHis Gln Ser Gln Gln 20 25 301 36 PRT Conus litteratus 301 His Arg ValPhe His Leu Asp Asn Thr Tyr Leu Lys Ile Pro Ile Cys 1 5 10 15 Ala TrpLys Val Cys Pro Pro Thr Pro Trp Arg Arg Arg Asp Leu Lys 20 25 30 Lys ArgAsn Lys 35 302 50 PRT Conus litteratus 302 Ser Pro Val Ser Thr Pro TyrPro Glu Phe His Leu Asp Glu Pro Tyr 1 5 10 15 Leu Lys Ile Pro Val CysIle Trp Lys Ile Cys Pro Pro Asn Leu Leu 20 25 30 Arg Arg Arg Asp Leu LysLys Arg Asn Lys Val Arg Gln Thr Thr Ala 35 40 45 Thr Thr 50 303 26 PRTConus coronatus 303 Leu Ser Asp Gly Arg Asp Trp Thr Gly Tyr Ile Cys IleTrp Lys Ala 1 5 10 15 Cys Pro Arg Pro Pro Trp Ile Pro Pro Lys 20 25 30429 PRT Conus chaldaeus 304 Leu Ser Glu Gly Arg Asn Ser Thr Val His IleCys Met Trp Lys Val 1 5 10 15 Cys Pro Pro Pro Pro Trp Arg Arg Pro HisGly Gln Arg 20 25 305 29 PRT Conus chaldaeus 305 Leu Ser Glu Gly Arg AsnSer Thr Val His Ile Cys Thr Trp Lys Val 1 5 10 15 Cys Pro Pro Pro ProTrp Arg Arg Pro His Gly Gln Arg 20 25 306 13 PRT Unknown unknown Conusspecies 306 Glx Cys Met Trp Lys Arg Cys Ile Pro Asp Gln Ser Arg 1 5 10307 15 PRT Unknown unknown Conus species 307 Val Asp Ile Cys Asn Trp ArgIle Cys Ala Pro Asn Pro Leu Arg 1 5 10 15 308 13 PRT Conus geographusPEPTIDE (1)..(13) Xaa may be Trp (D or L) 308 Leu Cys Phe Xaa Lys SerCys Arg Pro Tyr Pro Trp Arg 1 5 10 309 16 PRT Conus magus PEPTIDE(1)..(16) Xaa may be Trp (D or L) 309 Leu Phe Cys Phe Xaa Trp Lys SerCys Trp Pro Arg Pro Tyr Trp Arg 1 5 10 15 310 16 PRT Conus magus PEPTIDE(1)..(16) Xaa may be Trp (D or L) 310 Leu Phe Cys Phe Xaa Lys Ser CysTrp Pro Arg Pro Tyr Pro Trp Arg 1 5 10 15 311 15 PRT Conus magus PEPTIDE(1)..(15) Xaa may be Phe (D or L) 311 Leu Xaa Cys Phe Trp Lys Ser CysTrp Pro Arg Pro Tyr Trp Arg 1 5 10 15 312 15 PRT Conus magus PEPTIDE(1)..(15) Xaa at residue 2 may be Phe (D or L); Xaa at residue 5 may beTrp (D or L) 312 Leu Xaa Cys Phe Xaa Lys Ser Cys Trp Pro Arg Pro Tyr TrpArg 1 5 10 15 313 11 PRT Conus magus PEPTIDE (1)..(11) Xaa may be Phe (Dor L) 313 Leu Xaa Cys Phe Trp Lys Ser Cys Trp Pro Arg 1 5 10 314 11 PRTConus magus PEPTIDE (1)..(11) Xaa may be Trp (D or L) 314 Leu Phe CysPhe Xaa Lys Ser Cys Trp Pro Arg 1 5 10 315 11 PRT Conus magus PEPTIDE(1)..(11) Xaa at residue 2 may be Phe (D or L); Xaa at residue 5 may beTrp (D or L) 315 Leu Xaa Cys Phe Xaa Lys Ser Cys Trp Pro Arg 1 5 10 3169 PRT Conus magus PEPTIDE (1)..(9) Xaa may be Phe (D or L) 316 Leu XaaCys Phe Trp Lys Ser Cys Trp 1 5 317 9 PRT Conus magus PEPTIDE (1)..(9)Xaa may be Trp (D or L) 317 Leu Phe Cys Phe Xaa Lys Ser Cys Trp 1 5 3189 PRT Conus magus PEPTIDE (1)..(9) Xaa at residue 2 may be Phe (D or L);Xaa at residue 5 may be Trp (D or L) 318 Leu Xaa Cys Phe Xaa Lys Ser CysTrp 1 5 319 10 PRT Conus magus PEPTIDE (1)..(10) Xaa may be Trp (D or L)319 Phe Cys Phe Xaa Lys Ser Cys Trp Pro Arg 1 5 10 320 10 PRT Conusmagus PEPTIDE (1)..(10) Xaa may be Lys (D or L) 320 Phe Cys Phe Trp XaaSer Cys Trp Pro Arg 1 5 10 321 10 PRT Conus magus PEPTIDE (1)..(10) Xaamay be Trp (D or L) 321 Phe Cys Phe Xaa Phe Ser Cys Trp Pro Arg 1 5 10322 10 PRT Conus magus 322 Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg 1 510 323 21 PRT Conus purpurascens PEPTIDE (1)..(21) Xaa may be Trp (D orL) 323 Glu Ser Asn Gly Val Glu Ile Cys Met Xaa Lys Val Cys Pro Pro Ser 15 10 15 Pro Trp Arg Arg Ser 20 324 14 PRT Conus striatus PEPTIDE(1)..(14) Xaa may be Trp (D or L) 324 Met Glu Cys Tyr Xaa Lys Ala CysArg Pro Thr Leu Ser Arg 1 5 10 325 16 PRT Conus striatus PEPTIDE(1)..(16) Xaa may be Trp (D or L) 325 Phe Glu Leu Lys Cys Ile Xaa LysPhe Cys Thr Ile Tyr Pro Ser Arg 1 5 10 15 326 18 PRT Conus striatusPEPTIDE (1)..(18) Xaa may be Trp (D or L) 326 Phe Glu Leu Lys Cys IleXaa Lys Phe Cys Thr Ile Tyr Pro Ser Arg 1 5 10 15 Pro Phe 327 14 PRTConus tulipa PEPTIDE (1)..(14) Xaa may be Trp (D or L) 327 Thr Val TyrIle Cys Met Xaa Lys Val Cys Pro Pro Ser Pro 1 5 10 328 22 PRT Conusaurisiacus PEPTIDE (1)..(22) Xaa may be Trp (D or L) 328 Ser Asp Ser SerAsp Gln Lys Ala Gln Ile Cys Ile Xaa Lys Val Cys 1 5 10 15 Pro Pro ProPro Trp Arg 20 329 16 PRT Conus consors PEPTIDE (1)..(16) Xaa may be Trp(D or L) 329 Gly Ala Gln Ile Cys Ile Xaa Lys Val Cys Pro Pro Ser Pro TrpArg 1 5 10 15 330 30 PRT Conus musicus PEPTIDE (1)..(30) Xaa may be Trp(D or L) 330 Met Phe Pro Ser Leu Ala Leu Gly Pro Gly Gly Asp Val Ile CysArg 1 5 10 15 Xaa Lys Val Cys Pro Pro Thr Pro Trp Lys Arg Leu Ile Lys 2025 30 331 24 PRT Conus flavidus PEPTIDE (1)..(24) Xaa may be Trp (D orL) 331 Val Asp Ile Cys Asn Xaa Arg Ile Cys Ala Pro Asn Pro Leu Arg Arg 15 10 15 His Asp Leu Lys Lys Gly Asn Asn 20 332 15 PRT Conus flavidusPEPTIDE (1)..(15) Xaa may be Trp (D or L) 332 Val Asp Ile Cys Asn XaaArg Ile Cys Ala Pro Asn Pro Leu Arg 1 5 10 15 333 22 PRT Conusgeographus PEPTIDE (1)..(22) Xaa may be Trp (D or L) 333 Arg Leu Phe CysPhe Xaa Lys Ser Cys Thr Trp Arg Pro Tyr Pro Trp 1 5 10 15 Arg Arg ArgAsp Leu Asn 20 334 17 PRT Conus generalis DISULFID (4)..(14) 334 Ser LeuTrp Cys Val Cys Pro Phe Arg Val Cys Pro Pro Cys His Gly 1 5 10 15 Arg335 17 PRT Conus generalis DISULFID (6)..(14) 335 Ser Leu Trp Cys ValCys Pro Phe Arg Val Cys Pro Pro Cys His Gly 1 5 10 15 Arg 336 15 PRTConus generalis PEPTIDE (1)..(15) Xaa may be Phe (D or L) 336 Ser LeuTrp Cys Val Cys Pro Xaa Arg Val Cys Pro Pro Cys His 1 5 10 15 337 15 PRTConus generalis PEPTIDE (1)..(15) Xaa may be Phe (D or L) 337 Ser LeuTrp Cys Val Cys Pro Xaa Arg Val Cys Pro Pro Cys His 1 5 10 15 338 6 PRTConus magus PEPTIDE (1)..(6) Xaa at residues 2 and 5 may be any aminoacid; Xaa at residue 3 may be Trp (D or L) or bromo-Trp (D or L) 338 CysXaa Xaa Lys Xaa Cys 1 5 339 6 PRT Conus generalis PEPTIDE (1)..(6) Xaamay be Phe (D or L) 339 Cys Pro Xaa Arg Val Cys 1 5 340 21 PRT Conusebraeus 340 Leu Ser Gly Gly Thr Tyr Ser Arg Val Asp Thr Cys Ile Trp LysVal 1 5 10 15 Cys Pro Gln Ser Pro 20

What is claimed is:
 1. An isolated peptide selected from the groupconsisting of: (a) a peptide selected from the group consisting ofpeptides comprising amino acid sequences set forth in SEQ ID NOs:3, 6,9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60,63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111,114, 117, 120, 123, 126, 129, 132, 135, 138, 141, 144, 147, 150, 153,156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195,198, 201, 204, 207, 210, 216, 219, 222, 225, 228-287, 289-315, 319-321,323-337 and 340; and (b) analogs and derivatives of the peptide in (a).2. The peptide of claim 1, wherein Xaa1 is Glu or γ-carboxy-Glu, Xaa2 isGln or pyro-Glu, Xaa3 is Pro or trans-4-hydroxy-Pro, Xaa4 is D or L Trpor D or L 6-bromo-Trp, and Xaa5 is Tyr, mono-iodo-Tyr, ¹²⁵I-Tyr,di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr.
 3. The peptide derivative ofclaim 1, in which Arg residues may be substituted by Lys, omithine,homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residuesmay be substituted by Arg, ornithine, homoarginine, nor-Lys, or anysynthetic basic amino acid; the Tyr residues may be substituted withmeta-Tyr, ortho-Tyr, nor-Tyr, ¹²⁵I-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic hydroxycontaining amino acid; the Ser residues may be substituted with Thr orany synthetic hydroxylated amino acid; the Thr residues may besubstituted with Ser or any synthetic hydroxylated amino acid; the Pheresidues may be D or L, may be substituted at the ortho, meta, and/orpara positions with a halogen or may be substituted with any syntheticaromatic amino acid; the Trp residues may be substituted with Trp (D),neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or any aromaticsynthetic amino acid; the Asn, Ser, Thr or Hyp residues may besubstituted with a glycan; the halogen may be iodo, chloro, fluoro orbromo; the Tyr residues may also be substituted with the 3-hydroxyl or2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) andcorresponding O-sulpho- and O-phospho-derivatives; the acidic amino acidresidues may be substituted with any synthetic acidic amino acid, e.g.,tetrazolyl derivatives of Gly and Ala; the Leu may be substituted withLeu (D); the Glu residues may be substituted with Gla or Asp; the acidicamino acid residues may be substituted with any synthetic acidic aminoacid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln maybe substituted with pyro-glutamate (Z); the aliphatic amino acids may besubstituted by synthetic derivatives bearing non-natural aliphaticbranched or linear side chains C_(n)H_(2n+2) up to and including n=8;the Met residues may be substituted with nor-leucine (Nle); the Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L); basic residues in the backbonemay be D or L configuration; the central Trp residue within thebeta-turn is preferably epimerized to the D-form; pairs of Cys residuesmay be replaced pairwise with isoteric lactam or ester-thioetherreplacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu orAsp) or Cys/Ala combinations; and individual Cys residues may bereplaced with homoCys, seleno-Cys or penicillamine, so that disulfidebridges may be formed between Cys-homoCys or Cys-penicillamine, orhomoCys-penicllamine.
 4. The peptide derivative of claim 3, wherein theglycan is any N-, S- or O-linked mono-, di-, tri-, poly- oroligosaccharide that can be attached to any hydroxy, amino or thiolgroup of natural or modified amino, wherein the monosaccharides makingup the glycan can be unmodified or modified D-allose, D-altrose,D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose,D-galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc),D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose, wherein theglycosidic linkage is beta and 1-4 or 1-3, preferably 1-3, and whereinthe linkage between the glycan and the amino acid may be alpha or beta,preferably alpha and is 1-.
 5. The peptide derivative of claim 4,wherein the modification may include one or more O-sulfate, O-phosphate,O-acetyl or acidic groups, and combinations thereof.
 6. The peptidederivative of claim 4, wherein the gylcan may also include similarpolyhydroxy groups, such as D-penicillamine 2,5 and halogenatedderivatives thereof or polypropylene glycol derivatives.
 7. Thederivative of the peptide of claim 1 in which the peptide is truncated.8. The peptide derivative of claim 3 in which the peptide derivative istruncated.
 9. The peptide derivative of claim 4 in which the peptidederivative is truncated.
 10. An peptide of claim 1 containing 4cysteines which are bridged as [1,4/2,3].
 11. An peptide of claim 1containing 4 cysteines which are bridged as [1,3/2,4].
 12. The peptideof claim 1, wherein the peptide is tagged with a radiolabel.
 13. Thepeptide derivative of claim 1 in which a basic or aromatic amino acid inthe beta turn is a D-isomer.
 14. The peptide derivative of claim 13 inwhich the peptide derivative is truncated.
 15. The peptide of claim 13,wherein the peptide is tagged with a radiolabel.
 16. The peptide ofclaim 14, wherein the peptide is tagged with a radiolabel.
 17. Anisolated nucleic acid encoding a β-superfamily conopeptide propeptideselected from the group of propeptides comprising amino acid sequencesset forth in SEQ ID NO:2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38,41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92,95, 98, 101, 104, 107, 110, 113, 116, 119, 122, 125, 128, 131, 134, 137,140, 143, 146, 149, 152, 155, 158, 161, 164, 167, 170, 173, 176, 179,182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 215, 218, 221, 224,and
 227. 18. The isolated nucleic acid of claim 17 wherein the nucleicacid comprises a nucleotide sequence selected from the group ofnucleotide sequences set forth in SEQ ID NO:1, 4, 7, 10, 13, 16, 19, 22,25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, 58, 61, 64, 67, 70, 73, 76,79, 82, 85, 88, 91, 94, 97, 100, 103, 106, 109, 112, 115, 118, 121, 124,127, 130, 133, 136, 139, 142, 145, 148, 151, 154, 157, 160, 163, 166,169, 172, 175, 178, 181, 184, 187, 190, 193, 196, 199, 202, 205, 208,214, 217, 220, 223, and
 226. 19. An isolated β-superfamily conopeptidepropeptide selected from the group of propeptides comprising amino acidsequences set forth in SEQ ID NO:2, 5, 8, 11, 14, 17, 20, 23, 26, 29,32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83,86, 89, 92, 95, 98, 101, 104, 107, 110, 113, 116, 119, 122, 125, 128,131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 167, 170,173, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 215,218, 221, 224, and
 227. 20. A method for treating cancer which comprisesadministering an active agent or a pharmaceutically acceptable saltthereof to an individual having cancer, wherein said active agent is apeptide tagged with a radionuclide, wherein said peptide is aβ-superfamily conotoxin.
 21. The method of claim 20, wherein saidβ-superfamily conotoxin is selected from the group consisting of: (a) apeptide selected from the group consisting of peptides comprising aminoacid sequences set forth in SEQ ID NO:3, 6, 9, 12, 15, 18, 21, 24, 27,30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81,84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126,129, 132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168,171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210,216, 219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and (b)analogs and derivatives of the peptide in (a).
 22. The method of claim20, wherein the radionuclide is selected from the group consisting of¹³¹iodine, ¹²³iodine, ^(99m)technicium, ¹¹¹indium, ¹⁸⁸rhenium,186rhenium, ⁶⁷gallium, ⁹⁰yttrium, ¹⁰⁵rhodium, ⁸⁹strontium, ¹⁵³samarium,²¹¹astatine, ²¹²bismuth, ²¹³bismuth, ¹⁷⁷ lutetium, ⁶⁴copper, 67copper,⁴⁷scandium, ¹⁰⁹palladium.
 23. The method of claim 21, wherein theradionuclide is selected from the group consisting of ¹³¹iodine,¹²³iodine, ^(99m)technicium, ¹¹¹indium, ¹⁸⁸rhenium, ¹⁸⁶rhenium,⁶⁷gallium, ⁹⁰yttrium, ¹⁰⁵rhodium, ⁸⁹strontium, ¹⁵³samarium, ²¹¹astatine,²¹²bismuth, ²¹³bismuth, ¹⁷⁷ lutetium, ⁶⁴copper, ⁶⁷copper, ⁴⁷scandium,¹⁰⁹palladium.
 24. The method of claim 21, wherein the active agent apeptide derivative in which Arg residues may be substituted by Lys,ornithine, homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residuesmay be substituted by Arg, ornithine, homoarginine, nor-Lys, or anysynthetic basic amino acid; the Tyr residues may be substituted withmeta-Tyr, ortho-Tyr, nor-Tyr, ¹²⁵I-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic hydroxycontaining amino acid; the Ser residues may be substituted with Thr orany synthetic hydroxylated amino acid; the Thr residues may besubstituted with Ser or any synthetic hydroxylated amino acid; the Pheresidues may be D or L, may be substituted at the ortho, meta, and/orpara positions with a halogen or may be substituted with any syntheticaromatic amino acid; the Trp residues may be substituted with Trp (D),neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or any aromaticsynthetic amino acid; the Asn, Ser, Thr or Hyp residues may besubstituted with a glycan; the halogen may be iodo, chloro, fluoro orbromo; the Tyr residues may also be substituted with the 3-hydroxyl or2-hydroxylisomers (meta-Tyr or ortho-Tyr, respectively) andcorresponding O-sulpho- and O-phospho-derivatives; the acidic amino acidresidues may be substituted with any synthetic acidic amino acid, e.g.,tetrazolyl derivatives of Gly and Ala; the Leu may be substituted withLeu (D); the Glu residues may be substituted with Gla or Asp; the acidicamino acid residues may be substituted with any synthetic acidic aminoacid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln maybe substituted with pyro-glutamate (Z); the aliphatic amino acids may besubstituted by synthetic derivatives bearing non-natural aliphaticbranched or linear side chains C_(n)H_(2n+2) up to and including n=8;the Met residues may be substituted with nor-leucine (Nle); the Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L); basic residues in the backbonemay be D or L configuration; the central Trp residue within thebeta-turn is preferably epimerized to the D-form; pairs of Cys residuesmay be replaced pairwise with isoteric lactam or ester-thioetherreplacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu orAsp) or Cys/Ala combinations; and individual Cys residues may bereplaced with homoCys, seleno-Cys or penicillamine, so that disulfidebridges may be formed between Cys-homoCys or Cys-penicillamine, orhomoCys-penicllamine.
 25. The method of claim 24, wherein the the glycanis any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharidethat can be attached to an hydroxy, amino or thiol group of natural ormodified amino, wherein the monosaccharides making up the glycan can beunmodified or modified D-allose, D-altrose, D-glucose, D-mannose,D-gulose, D-idose, D-galactose, D-talose, D-galactosamine,D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine(GalNAc), D-fucose or D-arabinose, wherein the glycosidic linkage isbeta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between theglycan and the amino acid may be alpha or beta, preferably alpha and is1-.
 26. The method of claim 21, wherein the peptide has activity atsomatostatin receptors.
 27. A method of alleviating pain in anindividual which comprises administering to an individual who is eitherexhibiting pain or is about to be subjected to a pain-causing event apain-alleviating amount of an active agent or a pharmaceuticallyacceptible salt thereof, wherein said active agent is a β-superfamilyconotoxin.
 28. The method of claim 27, wherein the βsuperfamilyconotoxin is selected from the group consisting of: (a) a peptideselected from the group consisting of peptides comprising amino acidsequences set forth in SEQ ID NO:3, 6, 9, 12, 15, 18, 21, 24, 27, 30,33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84,87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129,132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168, 171,174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210, 216,219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and (b)analogs and derivatives of the peptide in (a).
 29. The method of claim28, wherein the active agent a peptide derivative in which Arg residuesmay be substituted by Lys, ornithine, homoarginine, nor-Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any syntheticbasic amino acid; the Lys residues may be substituted by Arg, ornithine,homoarginine, nor-Lys, or any synthetic basic amino acid; the Tyrresidues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, ¹²⁵I-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr orany synthetic hydroxy containing amino acid; the Ser residues may besubstituted with Thr or any synthetic hydroxylated amino acid; the Thrresidues may be substituted with Ser or any synthetic hydroxylated aminoacid; the Phe residues may be D or L, may be substituted at the ortho,meta, and/or para positions with a halogen or may be substituted withany synthetic aromatic amino acid; the Trp residues may be substitutedwith Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or anyaromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may besubstituted with a glycan; the halogen may be iodo, chloro, fluoro orbromo; the Tyr residues may also be substituted with the 3-hydroxyl or2-hydroxylisomers (meta-Tyr or ortho-Tyr, respectively) andcorresponding O-sulpho- and O-phospho-derivatives; the acidic amino acidresidues may be substituted with any synthetic acidic amino acid, e.g.,tetrazolyl derivatives of Gly and Ala; the Leu may be substituted withLeu (D); the Glu residues may be substituted with Gla or Asp; the acidicamino acid residues may be substituted with any synthetic acidic aminoacid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln maybe substituted with pyro-glutamate (Z); the aliphatic amino acids may besubstituted by synthetic derivatives bearing non-natural aliphaticbranched or linear side chains C_(n)H_(2n+2) up to and including n=8;the Met residues may be substituted with nor-leucine (Nle); the Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L); basic residues in the backbonemay be D or L configuration; the central Trp residue within thebeta-turn is preferably epimerized to the D-form; pairs of Cys residuesmay be replaced pairwise with isoteric lactam or ester-thioetherreplacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu orAsp) or Cys/Ala combinations; and individual Cys residues may bereplaced with homoCys, seleno-Cys or penicillamine, so that disulfidebridges may be formed between Cys-homoCys or Cys-penicillamine, orhomoCys-penicllamine.
 30. The method of claim 29, wherein the the glycanis any N—, S- or O-linked mono-, di-, tri-, poly- or oligosaccharidethat can be attached to any hydroxy, amino or thiol group of natural ormodified amino, wherein the monosaccharides making up the glycan can beunmodified or modified D-allose, D-altrose, D-glucose, D-mannose,D-gulose, D-idose, D-galactose, D-talose, D-galactosamine,D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine(GalNAc), D-fucose or D-arabinose, wherein the glycosidic linkage isbeta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between theglycan and the amino acid may be alpha or beta, preferably alpha and is1-.
 31. The method of claim 27, wherein the pain is visceral pain.
 32. Amethod for treating or preventing disorders associated with a disorderselected from the group consisting of voltage-gated ion channeldisorders, ligand-gated ion channel disorders and receptor disorders,such as disorders of G-protein coupled receptors, in an individual whichcomprises administering to an individual in need thereof atherapeutically effective amount of an active agent or apharmaceutically acceptible salt thereof, wherein the active agent is aβ-superfamily conotoxin.
 33. The method of claim 32, wherein theβ-superfamily conotoxin is selected from the group consisting of: (a) apeptide selected from the group consisting of peptides comprising aminoacid sequences set forth in SEQ ID NO:3, 6, 9, 12, 15, 18, 21, 24, 27,30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81,84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126,129, 132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168,171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210,216, 219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and (b)analogs and derivatives of the peptide in (a).
 34. The method of claim33, wherein the active agent a peptide derivative in which Arg residuesmay be substituted by Lys, ornithine, homoarginine, nor-Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any syntheticbasic amino acid; the Lys residues may be substituted by Arg, omithine,homoarginine, nor-Lys, or any synthetic basic amino acid; the Tyrresidues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, ¹²⁵I-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr orany synthetic hydroxy containing amino acid; the Ser residues may besubstituted with Thr or any synthetic hydroxylated amino acid; the Thrresidues may be substituted with Ser or any synthetic hydroxylated aminoacid; the Phe residues may be D or L, may be substituted at the ortho,meta, and/or para positions with a halogen or may be substituted withany synthetic aromatic amino acid; the Trp residues may be substitutedwith Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or anyaromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may besubstituted with a glycan; the halogen may be iodo, chloro, fluoro orbromo; the Tyr residues may also be substituted with the 3-hydroxyl or2-hydroxylisomers (meta-Tyr or ortho-Tyr, respectively) andcorresponding O-sulpho- and O-phospho-derivatives; the acidic amino acidresidues may be substituted with any synthetic acidic amino acid, e.g.,tetrazolyl derivatives of Gly and Ala; the Leu may be substituted withLeu (D); the Glu residues may be substituted with Gla or Asp; the acidicamino acid residues may be substituted with any synthetic acidic aminoacid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln maybe substituted with pyro-glutamate (Z); the aliphatic amino acids may besubstituted by synthetic derivatives bearing non-natural aliphaticbranched or linear side chains C_(n)H_(2n+2) up to and including n=8;the Met residues may be substituted with nor-leucine (Nle); the Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L); basic residues in the backbonemay be D or L configuration; the central Trp residue within thebeta-turn is preferably epimerized to the D-form; pairs of Cys residuesmay be replaced pairwise with isoteric lactam or ester-thioetherreplacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu orAsp) or Cys/Ala combinations; and individual Cys residues may bereplaced with homoCys, seleno-Cys or penicillamine, so that disulfidebridges may be formed between Cys-homoCys or Cys-penicillamine, orhomoCys-penicllamine.
 35. The method of claim 34, wherein the the glycanis any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharidethat can be attached to any hydroxy, amino or thiol group of natural ormodified amino, wherein the monosaccharides making up the glycan can beunmodified or modified D-allose, D-altrose, D-glucose, D-mannose,D-gulose, D-idose, D-galactose, D-talose, D-galactosamine,D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine(GalNAc), D-fucose or D-arabinose, wherein the glycosidic linkage isbeta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between theglycan and the amino acid may be alpha or beta, preferably alpha and is1-.
 36. The method of claim 32, wherein the disorder is a G-proteincoupled receptor disorder.
 37. The method of claim 36, wherein theG-protein coupled receptor is selected from the group consisting of sst,cortistatin (CST), melanocortin (MC_(x)R, wherein x=1, 2, 3, 4, 5),opioid (μ, δ, κ), neurokinin, bradykinin, galanin, CCK_(A), CCK_(B),endothelin, serotonin, adrenergic receptors, angiotensin,neuropeptide-Y, sigma1, sigma2, oxytocin, CGRP, GRPR, histamine,imidazoline, neurotensin, VIP, vasopressin, substance K, chemokinereceptors, CRF₁, CRF_(2a), CRF_(2β), CRF_(2γ), CRF-BP, orexin,urotensin, glycoprotein IIb/IIIa, thrombin receptors and orphan GPCRs.38. The method of claim 36, wherein the GPCR is selected from the groupconsisting of MCH₂R/SLT, SP1999/P₂Y₁₂, CRTH₂, NPFF₁, NPFF₂, HH₄R,h-GPR₅₄, CysLT₂, neuromedin receptors, BLTR₂, G₂A, TA₁, LTB₄, ghrelin,motilin MTL-R, purinergic receptors, muscarinic receptors, ORL-1,apelin, CB₁, CB₂ and GPCRs of orphan status having no known cognateligand.
 39. The method of claim 32, wherein the disorder is selectedfrom the group consisting of cancer, neoplasm, solid tumor, diabeticnephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis,angiogenesis disorder, diabetes mellitus, endocrine tumor, diarrhea,pancreatic disease, prostate tumor, bleeding and apoptosis.
 40. Themethod of claim 39, wherein the peptide has activity at somatostatinreceptors.
 41. The method of claim 32, wherein the disorder is selectedfrom the group consisting of inflammation, pain, diabetes, obesity,sexual dysfunction, acromegaly, glaucoma, cardiovascular, diabetic,retinopathy, depression, myocardial infarction, stroke, epilepsy,anorexia, wasting diseases, seborrheic dermatitis, schizophrenia, mooddisorders, chemotherapeutic induced emesis, disorders associated withchanges in blood pressure, immune disorders, nerve damage, acne, GIinfections, myocardial infarction, angina, thromboembolism andcardiovascular disease.
 42. The method of claim 41, wherein the peptidehas activity at somatostatin receptors or at melanocortin receptors. 43.The method of claim 32, wherein the receptor is LHRH.
 44. The method ofclaim 43, wherein the disorder is osteoporosis.
 45. The method of claim32, wherein the disorder is associated with a melanocortin system or MCRdysfunction.
 46. The method of claim 45, wherein the disorder isselected from the group consisting of erectile dysfunction, obesityinflammation and melanoma.
 47. The method of claim 45, wherein thepeptide contains a β-turn.
 48. The method of claim 47, wherein thepeptide is a β-Gel4.1 analogue, derivative thereof or pharmaceuticallyacceptable salt thereof, wherein the β-Gel4.1 analogue is selected fromthe group of peptides comprising an amino acid sequence set forth in SEQID NOs:334-337,.
 49. A method for identifying drug candidates for use astreating or preventing disorders associated with a disorder selectedfrom the group consisting of voltage-gated ion channel disorders,ligand-gated ion channel disorders and receptor disorders, such asdisorders of G-protein coupled receptors which comprises screening adrug candidate for its action at or partially at the same functionalsite as a β-superfamily conotoxin and capable of elucidation of similarfunctional response as said conotoxin.
 50. The method of claim 49,wherein the displacement of a labeled β-superfamily conotoxin from itsreceptor or other complex by a candidate drug agent is used to identifysuitable candidate drugs.
 51. The method of claim 49, wherein abiological assay on a test compound to determine the therapeuticactivity is conducted and compared to the results obtained from thebiological assay of a β-superfamily conotoxin.
 52. The method of claim49, wherein the binding affinity of a small molecule to the receptor ofa β-conotoxin is measured and compared to the binding affinity of aβ-superfamily conotoxin to its receptor.
 53. A method of identifyingcompounds that mimic the therapeutic activity of a superfamilyconotoxin, comprising the steps of: (a) conducting a biological assay ona test compound to determine the therapeutic activity; and (b) comparingthe results obtained from the biological assay of the test compound tothe results obtained from the biological assay of a β-superfamilyconotoxin.
 54. A method for characterizing a new site on a voltage-gatedion channel, a ligand-gated ion channel and a receptor, such as aG-protein coupled receptors which comprises contacting a peptide ofclaim 1 with a channel or receptor and measuring the binding of thepeptide with the channel or receptor or by measuring a functional invitro parameters such as fluorescence, phosphorescence andilluminescence.
 55. The method of claim 54, wherein the receptor is aG-protein coupled receptor.
 56. The method of claim 54, wherein thepeptide is radiolabeled.
 57. A method for designing a β-beta turnmimetic of a β-superfamily conotoxin containing a β-turn motif selectedfrom the group consistinf of (i) a —CX1X2KX1C— (SEQ ID NO:338) motif,wherein X1 is any amino acid and X2 is D or L Trp or D or L 6-bromo Trpand (ii) a —CPX3RVC— (SEQ ID NO:339) motif, wherein X3 is D or L Phe,which comprises replacing this motif with a non-peptide turn mimeticβ-turn scaffold and then attaching receptor binding domains containedwithin the N and C-terminal sequences of a β-superfamily conotoxin tothe β-turn scaffold to mimic the 3D spatial array within the nativeβ-superfamily conotoxin.
 58. A method for identifying a ligand whichbinds to an orphan G-protein coupled receptor (orphan GPCR) whichcomprises contacting a peptide of claim 1 or a radiolabeled derivativeof the peptide with an orphan GPCR and measuring the amount of bindingof the peptide to the orphan GPCR.
 59. The method of claim 58, whereinthe peptide is radiolabeled.
 60. The method of claim 59, wherein theradiolabel is selected from the group consisting of ³H and ¹²⁵I.
 61. Themethod of claim 58, which further comprises performing a homology searchfor the peptide which binds to the orphan GPCR to identify othercandidate ligands for testing.